Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[Cl:9].F[C:11](F)(F)[S:12](O)(=[O:14])=[O:13]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:12]([CH3:11])(=[O:14])=[O:13])=[C:4]([Cl:8])[C:3]=1[Cl:9]
Reactant: Clc1cccc(Cl)c1Cl
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Cl)c(Cl)c1Cl

Procedure:
A mixture of 133 g (1.38 mol) of methanesulfonic acid and 67 g (0.56 mol) of thionyl chloride was heated to reflux with stirring for one hour. The temperature increased from 50° C. to 160° C. as the reaction to form methanesulfonic acid anhydride progressed. The resulting mixture was cooled to below 50° C. and then 50.0 g (0.28 mol) of 1,2,3-trichlorobenzene and 4.2 g (0.028 mol) of trifluoromethanesulfonic acid were added. This mixture was heated with stirring and allowed to react at 140° C. for 18 hours and at 160° C. for 2 hours. The resulting mixture solidified on cooling. It was taken up in 600 mL of dichloromethane and the resulting solution was washed with 2×100 mL of water, 100 mL of 1 M aqueous sodium bicarbonate solution, and 100 mL of water, dried over sodium sulfate, and concentrated by evaporation under reduced pressure to obtain 58.5 g of a 9:1 mixture of the title compound and its isomer. This was recrystallized from ethanol to obtain 46 g (63 percent of theory) of the title compound as a white solid melting at 159-160° C. The structure was confirmed by its 1H NMR spectrum (CDCl3): 8.02(d, 1H, J=8.6 Hz), 7.60(d, 1H, 8.7 Hz), 3.28(s, 3H) and its 13C NMR spectrum (CDCl3): 140.1, 138.5, 134.6, 132.8, 126.7, 42.6.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[Cl:9][C:10]1[C:15](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=[C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[N:11]=1>CS(C)=O>[Cl:9][C:10]1[C:15]([C@@H:16]2[CH2:2][C@H:17]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=[C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)[N:11]=1
Reactant: CCOC(=O)/C=C/c1ccc(-c2cccc(C(F)(F)F)c2)nc1Cl
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)nc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Trimethyl sulfoxonium iodide (4.6 g, 21.25 mmol) was added slowly in small portions over a period of 20 min, to a suspension of sodium hydride (850 mg, 21.25 mmol) in dry DMSO (120 mL) at RT stirred for 1 h, till the formation of clear solution. A solution of (E)-ethyl 3-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)acrylate (6.3 g, 17.71 mmol) in dry DMSO (100 mL) was added slowly dropwise and stirred at RT for 30 mins. After completion, the reaction mixture was poured into ice water (100 mL), extracted with EtOAc (2×100 mL). The combined extracts were washed with ice water (2×100 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and evaporated to afford trans-ethyl 2-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanecarboxylate (crude) (5.5 g) as reddish brown liquid. The crude was carried to next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]1([N:15]=[C:16]=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([NH:15][C:16]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[SH:8])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1S
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccccc1S
Yield: 85 %

Procedure:
2-{[(Phenylamino)carbonyl]amino}thiophenol was prepared from 2-5 aminothiophenol (200 mg, 1.6 mmol) and phenyl isocyanate according to the procedure in General Method A. The product was purified by precipitation from toluene and filtering to afford the titled compound (330 mg, 85%). mp: 194.5° C.; 1H NMR (CD3OD/CDCl3): d 7.48-7.26 (m, 4H), 7.25-7.10 (m, 3H), 7.04-6.79 (m, 2H); EI-MS m/z 244 (M+H)+; Anal. (C13H12N2OS) C, H, N.
Reaction SMILES: C1N(CCO)CCN([CH2:10][CH2:11]S(O)(=O)=O)C1.[F-].[K+].[CH2:18](S)[C@@H:19](O)[C@H:20](O)[CH2:21]S>>[CH3:18][C:19](=[CH:20][CH2:21][CH2:18]/[C:19](=[CH:20]/[CH2:21][CH2:10]/[C:11](=[CH:10]/[CH2:11][CH2:18]/[CH:19]=[C:20](/[CH2:21][CH2:18]/[CH:19]=[C:20](/[CH2:10][CH2:11][CH:10]=[C:10]([CH3:11])[CH3:11])\[CH3:21])\[CH3:21])/[CH3:20])/[CH3:19])[CH3:18]
Reactant: O=S(=O)(O)CCN1CCN(CCO)CC1
Reactant: O[C@H](CS)[C@H](O)CS
Agent: [F-]
Agent: [K+]
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C=C(\C)CC/C=C(\C)CCC=C(C)C

Procedure:
Buffer mixture contains 270 mM HEPES, pH 7.5, 20 mM Potassium fluoride and 5.4 mM Dithiothreitol(DTT). 55 μL of this mixture was used per assay. The final concentrations of HEPES, KF and DTT in the assay are 150 mM, 11 I mM and 3 mM respectively.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[C:7]=1[N:13]=[C:14]=[S:15]>>[NH2:3][CH2:2][CH2:1][NH:4][C:14]([NH:13][C:7]1[C:8]([Br:12])=[CH:9][CH:10]=[CH:11][C:6]=1[Br:5])=[S:15]
Reactant: S=C=Nc1c(Br)cccc1Br
Reactant: NCCN
Product: NCCNC(=S)Nc1c(Br)cccc1Br

Procedure:
In a similar manner to that described in Example 1, ethylenediamine was reacted with 2,6-dibromophenylisothiocyanate to yield 1-(2-aminoethyl)-3-(2,6-dibromophenyl)thiourea, melting point 155°-157°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.CC(C)([O-])C.[K+]>CN(C)C=O.O1CCCC1>[N+:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[O:22][C:19]1[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=1)([O-:14])=[O:13]
Reactant: Nc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc3c([N+](=O)[O-])cccc23)cc1
Temperature: 110 °C
Reaction time: 7 h
Yield: 58.8 %

Procedure:
4-Chloro-8-nitroquinoline (176 mg, 0.85 mmol) and 4-aminophenol (93 mg, 0.85 mmol) were dissolved in dimethylformamide, and to which 1.0 M potassium tert-butoxide (0.95 mL) in tetrahydrofuran was slowly added dropwise at room temperature, which was then heated and stirred at 110° C. for seven hours. When the reaction was completed, the resultant was extracted with ethyl acetate and aqueous sodium chloride, and the combined organic layers were dried with anhydrous sodium sulfate, and then filtered. The solvent was removed by vacuum distillation, and the residue was purified by a column chromatography (ethyl acetate/n-hexane=½) to obtain 140.6 mg of the desired compound as a reddish brown solid (yield 59.0%).
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.Cl[CH2:25][CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C(OCC)(=O)C>[C:31]([O:30][C:28]([CH2:27][CH2:26][CH2:25][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH2:11][CH3:12])=[O:9])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccccc1OCCCC(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 61.8 %

Procedure:
A mixture comprising ethyl salicylate (3.14 g, 18.9 mmol) and cesium carbonate (6.2 g, 18.9 mmol), dimethylformamide (25 mL) and tert-butyl 4-chlorobutyrate (4.08 g, 22.8 mmol) was heated at 70° C. and stirred for 12 hours. The mixture was partitioned between ethyl ether (100 mL) and water and the organic layer was separated and washed with additional water (3×) and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a colorless oil. The residue was purified by silica gel flash chromatography using pure hexane to (10:1) hexane:ethyl acetate to provide ethyl 2-(3-tert-butoxycarbonylpropoxy)benzoate (3.6 g, 62% yield) as a colorless oil; 1H NMR (300 MHz, CDCl3): 7.80 (d, 1H), 7.49 (tr, 1H), 7.00 (m, 2H), 4.40 (q, 2H), 4.10 (tr, 2H), 2.50 (tr, 2H), 2.10 (m, 2H), 1.45 (s, 9H), 1.40 (tr, 3H).
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[Cl-].[NH4+].[N-:10]=[N+:11]=[N-:12].[Na+]>C(O)C.O>[N:10]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[OH:7])=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: C1CCC2OC2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=NC1CCCCC1O
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a solution of cyclohexene oxide (150 g, 1.53 mol) in a mixture of ethanol (600 ml) and water (600 ml) is added ammonium chloride (168 g, 3.1 mol) followed by sodium azide (198 g, 3 mol). The resulting solution is stirred gently at 50° C. for 12 hours before being allowed to cool. The volatiles are removed in vacuo, and 6M hydrochloric acid (˜120 ml) is added to bring the reaction to pH 7. The reaction is extracted with ethyl acetate (2×750 ml), and the organic extracts are washed with brine (750 ml) and dried over sodium sulfate. Removal of the solvent in vacuo affords 2-azido-cyclohexan-1-ol as a slightly yellow oil (171.8 g, 80%), which is used in the following step without further purification.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3](=O)[CH2:4][C:5](OCC)=[O:6].[CH3:12][NH:13][NH2:14]>C1(C)C=CC=CC=1>[F:1][CH:2]([F:11])[C:3]1[CH2:4][C:5](=[O:6])[N:13]([CH3:12])[N:14]=1
Reactant: CCOC(=O)CC(=O)C(F)F
Reactant: CNN
Solvent: Cc1ccccc1
Product: CN1N=C(C(F)F)CC1=O
Temperature: 100 °C

Procedure:
Ethyl 4,4-difluoroacetoacetate (30.12 g, 0.172 mol) was stirred in toluene (600 mL) over ice water. Solution of N-methylhydrazine (7.6 mL, 0.14 mol) in toluene (200 mL) was added slowly, dropwise over 20 min. The reaction mixture was heated at 100° C. for 2 hours. The reaction mixture evaporated to dryness. The resulting material was triturated with methyl t-butylether/heptane to give 3-(difluoromethyl)-1-methyl-1H-pyrazol-5(4H)-one in three batches (total 10.7 g, 51%) as orange powder. This material was used without further purification for the next reaction.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:9][CH:10]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 24(t)] with benzyl bromide therer was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless, amorphous solid, which was used in the next step without characterization.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14](=[O:17])[NH:13][CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:18][O:19][CH:20]([O:25][CH3:26])[CH2:21][CH2:22][CH2:23]Br>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]([CH2:23][CH2:22][CH2:21][CH:20]([O:25][CH3:26])[O:19][CH3:18])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(CCCBr)OC
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(CCCN1CCN(C(=O)OC(C)(C)C)CCC1=O)OC
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 51.8 %

Procedure:
To a suspension of 60% sodium hydride in mineral oil (0.2 g, 5 mmole) in N,N-dimethylformamide (6 mL) was added 5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.0 g, 4.67 mmole). The reaction mixture was warmed at 50° C. for 5 minutes, and then at room temperature for 15 minutes. To the resulting solution was added 4-bromobutyraldehyde dimethyl acetal (0.99 g, 5 mmole). After the reaction mixture was stirred at room temperature for 16 hours, the solvent was removed, and the residue was partitioned between water and ethyl acetate. The organic phase was washed with water, dried (magnesium sulfate), and concentrated. The residue was dissolved in diethyl ether, and the suspension was filtered, and the filtrate was concentrated. Purification by silica gel chromatography, eluting with 2% methanol in chloroform, gave 4-(4,4-dimethoxybutyl)-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.8 g,) as a heavy syrup. Nmr: (chloroform-d) δ (ppm) 1.49, s, (9H); 2.64, m, 3H; 3.32, s (3H); 4.37, m, (1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9](I)[C:8]([O:12][CH2:13][O:14][CH3:15])=[C:7](Br)[CH:6]=1)[CH3:2].C(OC(=O)[C:22]1[CH:27]=[C:26](Br)[C:25]([O:29][CH2:30][O:31]C)=[C:24](Br)[CH:23]=1)C>>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:22]2[CH:27]=[CH:26][C:25]3[O:29][CH2:30][O:31][C:24]=3[CH:23]=2)[C:8]([O:12][CH2:13][O:14][CH3:15])=[C:7]([C:22]2[CH:23]=[CH:24][C:25]3[O:29][CH2:30][O:31][C:26]=3[CH:27]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Br)c(OCOC)c(Br)c1
Reactant: CCOC(=O)c1cc(Br)c(OCOC)c(I)c1
Product: CCOC(=O)c1cc(-c2ccc3c(c2)OCO3)c(OCOC)c(-c2ccc3c(c2)OCO3)c1

Procedure:
3,5-Bis-(3,4-methylenedioxyphenyl)-4-methoxymethoxybenzoic acid ethyl ester was prepared as a white solid (3.1 g, 42.4%) in a similar manner to Step 1 of Example 143 from a 2:1 mixture of 3-bromo-4-methoxymethoxy-5-iodobenzoic acid ethyl ester and 3,5-dibromo-4-methoxymethoxybenzoic acid ethyl ester. There also yielded 780 mg of the monoarylated product. 1H NMR (CDCl3) δ 1.37 (t, J=8.18 Hz, 3H); 2.80 (s, 3H); 4.36 (quartet, J=8.18 Hz, 2H); 4.46 (s, 2H); 6.00 (s, 4H); 6.87 (d, J=8.18 Hz, 2H); 7.05 (dd, J=8.18 Hz, 1.63 Hz, 2H); 7.11 (d, J=1.23 Hz, 2H); 7.95 (s, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:18]([CH3:20])[CH3:19])[C:15](=[O:17])[CH3:16])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)=O.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:39][C:40]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[C:45]([O:51][CH3:52])[C:41]=1[C:42]([NH2:44])=[O:43]>CC(N(C)C)=O>[CH3:52][O:51][C:45]1[CH:46]=[C:47]([O:49][CH3:50])[CH:48]=[C:40]2[C:41]=1[C:42](=[O:43])[NH:44][C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]3[CH2:13][CH2:12][CH:11]([N:14]([CH:18]([CH3:19])[CH3:20])[C:15](=[O:17])[CH3:16])[CH2:10][CH2:9]3)=[CH:21][CH:22]=1)=[N:39]2
Reactant: CC(=O)N(C(C)C)C1CCN(Cc2ccc(C=O)cc2)CC1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(CN4CCC(N(C(C)=O)C(C)C)CC4)cc3)nc2c1
Temperature: 130 °C
Reaction time: 5 h
Yield: 56 %

Procedure:
A mixture of N-(1-(4-formylbenzyl)piperidin-4-yl)-N-isopropylacetamide (0.770 g, 2.5 mmol), NaHSO3 (0.350 g, 3.3 mmol), and p-TsOH (0.100 g, 0.51 mmol) was added to a solution of 2-amino-4,6-dimethoxybenzamide (0.500 g, 2.5 mmol) in DMA (20 mL). The reaction was stirred at 130° C. for 5 hours and concentrated in vacuo. The residue was diluted with H2O and saturated NaHCO3, then extracted with CH2Cl2. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 1% to 10% MeOH/CH2Cl2, afforded the title compound (0.670 g, 56%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 12.02 (s, 1H), 8.13 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 6.74 (d, J=1.9 Hz, 1H), 6.54 (d, J=2.0 Hz, 1H), 3.85-3.95 (m, 7H), 3.43-3.71 (m, 3H), 2.55-3.00 (m, 3H), 1.97-2.09 (m, 5H), 1.70-1.77 (m, 1H), 1.58-1.61 (m, 1H), 1.25-1.30 (m, 4H), 1.11-1.13 (m, 3H). ESI MS m/z 479 [M+H]+.
Reaction SMILES: [C:1]([S:4][C:5]([CH3:19])([CH3:18])[CH:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(Cl)CCl.[Cl:24][C:25]1[CH:26]=[N+:27]([O-:50])[CH:28]=[C:29]([Cl:49])[C:30]=1[CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([S:4][C:5]([CH3:19])([CH3:18])[CH:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7]([O:9][C@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:42])[F:43])=[C:36]([O:44][CH2:45][CH:46]2[CH2:47][CH2:48]2)[CH:35]=1)[CH2:31][C:30]1[C:29]([Cl:49])=[CH:28][N+:27]([O-:50])=[CH:26][C:25]=1[Cl:24])=[O:8])(=[O:3])[CH3:2]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CC(=O)SC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)SC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-(acetylthio)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (693 mg, 2.38 mmol) was dissolved in DCM (10 ml). DMAP (73 mg, 0.59 mmol), EDC (342 mg, 1.79 mmol), and (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (500 mg, 1.19 mmol) were added, and the mixture stirred for 4 hours at RT. The reaction mixture was diluted with DCM and washed with NaHCO3 sat. sol. (10 ml), HCl 1N, brine, dried over Na2SO4 and evaporated under vacuum to give 1.06 g. Crude compound was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:4]=1[C:24]([O:26][CH3:27])=[O:25].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(O)(C)C>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:2][C:3]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:6]=[C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[C:4]=2[C:24]([O:26][CH3:27])=[O:25])[CH2:31][CH2:30]1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1c(CBr)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Solvent: CC(C)O
Product: COC(=O)c1c(CN2CCN(C)CC2)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Reaction time: 0.17 h
Yield: 23.6 %

Procedure:
To a suspension of methyl 6-bromomethyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (1.5 g) in isopropyl alcohol (15 ml) was added N-methylpiperazine (0.88 g) at 70° C. The reaction mixture was stirred for 10 minutes at the same temperature. After evaporating the solvent, the residue was dissolved in a mixture of chloroform (50 ml) and water (50 ml). The organic layer was separated, dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to column chromatography on alumina (100 g) eluting with chloroform. The fractions containing the object compound were combined and concentrated under reduced pressure. The residual crystal was recrystallized from a mixture of diethyl ether and ethanol to give methyl 6-(4-methylpiperazin-1-ylmethyl)-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (0.37 g).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])[CH2:2][CH3:3].[CH3:12][C:13]([CH3:15])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([C:4]1[CH:10]=[CH:9][C:7]2[O:8][C:13]([CH3:15])([CH3:12])[O:11][C:6]=2[CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(O)c(O)c1
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCc1ccc2c(c1)OC(C)(C)O2

Procedure:
The same procedures as described in Example 10 were carried out by using a mixture of 7.61 g (50 mM) of 4-n-propylcatechol, 15 ml of acetone, 30 mg of p-toluenesulfonic acid monohydrate and 15 ml of benzene. 5-n-Propyl-2,2-dimethyl-1,3-benzodioxol was obtained in the yield of 9.13 g (47 mM) as colorless transparent liquid having a boiling point of 82°-87° C./3 mmHg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](O)=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CO)C1
Reaction time: 14 h
Yield: 98.3 %

Procedure:
To a tetrahydrofuran (100 mL) solution of 1-(tert-butoxycarbonyl)-3-azetidinecarboxylic acid (2.0 g, 9.94 mmol), 10M-borane-dimethyl sulfide complex (2.98 mL, 29.8 mmol) was added at room temperature, and the mixture was stirred for 14 hours. The reaction liquor was poured onto ice water (100 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (Flash Chromatography System from Biotage AB, column size: 40S, 2% methanol/ethyl acetate), to obtain the title compound (1.83 g, 98%) as an oily matter.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[F:31][C:32]1[CH:33]=[CH:34][C:35](Br)=[N:36][CH:37]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:35]1[CH:34]=[CH:33][C:32]([F:31])=[CH:37][N:36]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Fc1ccc(Br)nc1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccc(F)cn2)c1

Procedure:
N-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (˜1 mmol) was used in Procedure A with 5-fluoro-2-bromopyridine (1 mmol). Purified by silica gel chromatography (5-45% ethyl acetate/hexanes) to yield N-(4-chloro-3-(5-fluoropyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a tan solid: MS (Q1) 409 (M)+.
Reaction SMILES: C(O[C:4](=O)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])C.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[SH:26]>O>[S:26]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:4]1[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:12](=[O:17])[C:13]([F:14])([F:15])[F:16]
Reactant: Nc1ccccc1S
Reactant: CCOC(=O)CC1CCCCN1C(=O)C(F)(F)F
Solvent: O
Product: O=C(N1CCCCC1Cc1nc2ccccc2s1)C(F)(F)F
Temperature: 90 °C
Reaction time: 1 h

Procedure:
[1-(2,2,2-Trifluoroethanoyl)piperidin-2-yl] acetic acid ethyl ester, D28 (1.34 g) and 2-aminothiophenol (1.50 g) were suspended in polyphosphoric acid (30 ml) and heated to 90° C. for 2 h with vigorous stirring. After cooling, the reaction mixture was poured into iced water and stirred vigorously for 1 h. The aqueous solution was then extracted several times with ethyl acetate. After drying (MgSO4), the solvent was removed in vacuo and the residue chromatographed (silica gel) to afford the title compound as an oil (1.2 g).