Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([CH2:15]O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][C@@H:12]([CH2:15][N:40]2[C:39](=[O:41])[C:38]3[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=3[C:36]2=[O:46])[CH2:13][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C

Procedure:
cis-(tert-Butoxy)-N-[4-(hydroxymethyl)cyclohexyl]carboxamide (0.5 g, 2.18 mmol) and resin-bound triphenyl phosphine (1.453 g, 4.36 mmol, 3 mmol/g resin) were suspended in 15 mL of dry THF. Phthalimide was added in 5 mL of THF followed by diisopropyl azodicarboxylate (DIAD) (0.858 mL, 4.36 mmol). The reaction was stirred at room temperature and monitored by LC-MS. After overnight stirring at room temperature, the resin was removed by filtration and washed multiple times with 5 mL portions of THF. The filtrate combined with washings was concentrated under reduced pressure. The product was purified using column chromatography on silica gel using 10% ethyl acetate in hexanes as eluent. The product was isolated as a white solid (0.486 g, 1.35 mmol, 62% yield) ES-MS (m/z) 359.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:10][CH2:11][CH2:12][O:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:3]=1
Reactant: COCCCCl
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCCOc1cccc(Br)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A mixture of 3-bromophenol (5 g, 29 mmol), 1-chloro-3-methoxypropane (4.33 g, 40 mmol) and K2CO3 (8 g, 57.8 mmol) in DMF (90 mL) was stirred at 100° C. for 2 h. the reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was taken up in t-BuME, and the organic layer was washed with aqueous NaOH (1N), water (50 mL) and brine. The organic layer was dried and concentrated to give 1-bromo-3-(3-methoxypropoxy)benzene (7 g, 99%). 1H-NMR (CDCl3): 2.02 (m, 2H), 3.33 (s, 3H), 3.54 (m, 2H), 4.02 (m, 2H), 6.82 (m, 1H), 7.11 (m, 3H).
Reaction SMILES: C(Cl)Cl.[C:4]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].[CH3:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(=O)([O-])O.[Na+]>[CH2:21]([N:20]([CH3:19])[C@H:15]1[CH2:16][CH2:17][C@H:12]([NH:11][C:9]([O:8][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:10])[CH2:13][CH2:14]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(Cc1ccccc1)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To 160 ml of a methylene chloride solution containing 16.93 g of 4-(tert-butoxycarbonylamino)cyclohexanone and 10.55 ml of N-methylbenzylamine was added 19.08 g of sodium triacetoxyborohydride under ice-cooling, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with an aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained residue was suspended in hexane and collected by filtration. This mother liquor was concentrated and the residue was purified by NH-silica gel chromatography (solvent: hexane-ethyl acetate (97:3 to 83:17)). The residue was further suspended in hexane and collected by filtration and combined with the filtered product to obtain 13.55 g of N′-benzyl-N-tert-butoxycarbonyl-N′-methyl-trans-1,4-cyclohexanediamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=2)[CH:6]=1.[CH3:25][N:26]1[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[N:28]=[CH:27]1>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=2)[S:31]([C:29]2[N:28]=[CH:27][N:26]([CH3:25])[CH:30]=2)(=[O:33])=[O:32])[CH:6]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CCCCc1ccc(CNCc2cccc(CC(=O)OC)c2)cc1
Product: CCCCc1ccc(CN(Cc2cccc(CC(=O)OC)c2)S(=O)(=O)c2cn(C)cn2)cc1

Procedure:
The title compound of Step B was prepared following the procedure described in Step B of Example 1 from {3-[(4-butyl-benzylamino)-methyl]-phenyl}-acetic acid methyl ester, prepared in Step A of Example 9, and 1-methyl-1H-imidazole-4-sulfonyl chloride. 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.34 (s, 1H), 7.18-7.02 (m, 8H), 4.38 (s, 4H), 3.71 (s, 3H), 3.68 (s, 3H), 3.52 (s, 2H), 2.55 (t, 2H), 1.55 (m, 2H), 1.32 (m, 2H), 0.91 (t, 3H); MS 470 (M+1).
Reaction SMILES: [CH:1]1[C:2]([C:23]([F:26])([F:25])[F:24])=[CH:3][C:4]([Cl:22])=[C:5]([N:8]2[N:12]=[C:11]([C:13]#[N:14])[C:10]([S+:15]([O-:20])[C:16]([F:19])([F:18])[F:17])=[C:9]2[NH2:21])[C:6]=1[Cl:7].[CH:27](OCC)(OCC)[O:28][CH2:29][CH3:30]>O>[C:13]([C:11]1[C:10]([S:15]([C:16]([F:19])([F:17])[F:18])=[O:20])=[C:9]([N:21]=[CH:27][O:28][CH2:29][CH3:30])[N:8]([C:5]2[C:4]([Cl:22])=[CH:3][C:2]([C:23]([F:24])([F:26])[F:25])=[CH:1][C:6]=2[Cl:7])[N:12]=1)#[N:14]
Reactant: CCOC(OCC)OCC
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1[S+]([O-])C(F)(F)F
Solvent: O
Product: CCOC=Nc1c(S(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C

Procedure:
A 12-L three-necked flask fitted with an overhead stirrer, heating mantle, water separator (e.g. Dean Stark trap) with condenser was placed under a nitrogen atmosphere and charged with 1.475 kg (3.37 moles) of fipronil and 6 L of triethyl orthoformate. The suspension was heated to reflux over 2.5 h, then at reflux for 3 h with collection and removal of the distillate. The mixture was cooled to room temperature, then evaporated under reduced pressure at a bath temperature of 60-80° C., then at 50° C. overnight. The resulting beige solid, 1.717 kg (95.8% by HPLC, 3.335 moles, 99% purity corrected yield) was used without further purification (m.p. about 63° C.).
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26]O[CH2:24][CH2:23]1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:57])[NH:37][C:38]2[CH:56]=[CH:55][C:41]([O:42][C:43]3[C:44]4[CH:51]=[C:50]([C:52](O)=[O:53])[NH:49][C:45]=4[N:46]=[CH:47][N:48]=3)=[CH:40][CH:39]=2)=[CH:31][CH:30]=1.[Cl-].[NH4+]>C(N(CC)CC)C.CN(C)C=O>[CH2:27]([N:22]([CH2:23][CH3:24])[CH2:21][CH2:20][CH2:19][NH:18][C:52]([C:50]1[NH:49][C:45]2[N:46]=[CH:47][N:48]=[C:43]([O:42][C:41]3[CH:55]=[CH:56][C:38]([NH:37][C:36]([NH:35][C:32]4[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=4)=[O:57])=[CH:39][CH:40]=3)[C:44]=2[CH:51]=1)=[O:53])[CH3:26]
Reactant: NCCCN1CCOCC1
Reactant: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ncnc3[nH]c(C(=O)O)cc23)cc1
Agent: [Cl-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNC(=O)c1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ncnc2[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
After adding 0.8 ml of dimethylformamide, 21 μl of triethylamine, 9.5 μl of diphenylphosphoryl azide (DPPA) and 6.5 μl of 4-(3-aminopropyl)morpholine to 12 mg of the 4-{4-[3-(4-fluorophenyl)ureido]phenoxy)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid synthesized in Production Example 164, the mixture was stirred at room temperature for 2 days. Saturated ammonium chloride was added, liquid separation and extraction were performed with an ethyl acetate-tetrahydrofuran mixed solvent, and the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered with plug cotton and concentrated to dryness to obtain 9 mg of the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:8]=[C:9]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([CH3:21])[CH:14]=2)[CH:10]=[N:11][CH:12]=1)[C:3]([F:6])([F:5])[F:4].C(N(CC)CC)C.[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30]>C(Cl)Cl>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([C:9]2[CH:8]=[C:7]([CH:2]([NH:1][S:31]([CH2:29][CH3:30])(=[O:33])=[O:32])[C:3]([F:4])([F:6])[F:5])[CH:12]=[N:11][CH:10]=2)=[CH:14][C:15]=1[CH3:21])#[N:18]
Reactant: Cc1cc(-c2cncc(C(N)C(F)(F)F)c2)ccc1C#N
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)NC(c1cncc(-c2ccc(C#N)c(C)c2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.8 %

Procedure:
To a solution of 4-(5-(1-amino-2,2,2-trifluoroethyl)pyridin-3-yl)-2-methylbenzonitrile (322 mg, 1.105 mmol) in CH2Cl2 (5.5 mL) at 0° C. was added triethylamine (462 μl, 3.32 mmol) and ethanesulfonyl chloride (115 μl, 1.216 mmol). The mixture was stirred for 16 h at room temperature. The mixture was quenched with saturated NaHCO3 and extracted with EtOAc two times, dried over magnesium sulfate, filtered, concentrated. The residue was purified via Biotage (10-50% EtOAc/heptane; SNAP25 column) giving the title compound (67 mg, 16%). LC-MS (M+1) 384.1. 1H NMR (400 MHz, MeOD) δ ppm 1.28 (t, J=7.33 Hz, 3H) 2.63 (s, 3H) 2.96-3.19 (m, 2H) 5.47 (q, J=7.89 Hz, 1H) 7.66-7.72 (m, 1H) 7.76-7.79 (m, 1H) 7.81 (d, J=8.02 Hz, 1H) 8.24-8.43 (m, 1H) 8.76 (d, J=2.27 Hz, 1H) 8.93 (d, J=2.21 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[N:13][N:14]([CH:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[C:5]=3[C:4]=2[N:3]=1.Cl[CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=[O:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[N:13][N:14]([CH:15]4[CH2:20][CH2:19][N:18]([CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH2:17][CH2:16]4)[C:5]=3[C:4]=2[N:3]=1
Reactant: Clc1ccc2ncc3nnn(C4CCNCC4)c3c2n1
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN1CCC(n2nnc3cnc4ccc(Cl)nc4c32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 8-chloro-1-(piperidin-4-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridine (100 mg, 0.35 mmol), 2-chloro-N,N-dimethylacetamide (46 mg, 0.38 mmol), and K2CO3 (97 mg, 1.04 mmol) in DMF (5 mL) was stirred at r.t. overnight. The solvent was removed, and the residue was extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na2SO4, and concentrated to afford crude 2-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-N,N-dimethylacetamide, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[SH:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([OH:19])[N:13]=1.[OH-].[K+]>>[F:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([OH:19])[N:13]=1
Reactant: Oc1cc(O)nc(S)n1
Reactant: Cc1cccc(CBr)c1F
Agent: [K+]
Agent: [OH-]
Product: Cc1cccc(CSc2nc(O)cc(O)n2)c1F

Procedure:
The subtitle compound was prepared as a yellow solid by the method of Example 39 step i) using 2-fluoro-3-methylbenzyl bromide (7.0 g), 2-mercaptopyrimidine-4,6-diol (5.0 g) and potassium hydroxide (1.93 g). Yield: 8.36 g.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1([C:8]#[N:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:11]1([Li])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.C(OCCCC)CCC.CO>[NH2:9][CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1([N:2]([CH3:10])[CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: [Li]c1ccccc1
Reactant: CN(C)C1(C#N)CCCC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCOCCCC
Solvent: C1CCOC1
Product: CN(C)C1(C(N)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(dimethylamino)cyclopentanecarbonitrile D1 (4 g; 28.9 mmol) in THF (30 ml) at −70° C. under argon was added dropwise a solution of phenyllithium in dibutylether (17.7 ml of a 1.8M solution; 32 mmol). The reaction mixture was allowed to warm to room temperature over 3 h., recooled to 0° C. and methanol added (30 ml) followed by careful addition of sodium borohydride (3.3 g; 87 mmol). After stirring at room temperature for 18 h, the reaction mixture was cooled to 0° C. and saturated aqueous sodium bicarbonate added. The organic phase was evaporated and the resulting slurry extracted three times with DCM (3×150 ml). The combined extracts were dried (Na2SO4), and evaporated to afford the crude product as a yellow oil (6.8 g). Half of the crude product was chromatographed on silica gel eluting with DCM-methanol (9/1) and DCM-2M ammonia in methanol mixtures (95/5 to 9/1 to 8/2) to afford the title product as a colourless oil (2.3 g). This oil was dissolved in diethyl ether (20 ml) and hydrogen chloride in diethylether was added at 0° C. After 20 min, the suspension was filtered to give the dihydrochloride salt (2.8 g) of the title product as a white solid. 1H NMR (DMSO) δ: 1.25 (2H, bs), 1.36 (2H, bs), 1.66-2.13 (4H, m), 2.64 (3H, s), 2.79 (3H, s), 4.92 (1H, bs), 7.32 (3H, m), 7.54 (2H, m), 8.95 (3H, bs), 10.82 (1H, bs).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])(O)(=O)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[C-:20]#[N:21].[Na+]>O.C([O-])(O)=O.[Na+]>[C:2]1([CH:1]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:20]#[N:21])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: C1CCNC1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: N#CC(c1ccccc1)N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of benzaldehyde (9.4 mmol) in H2O (6 mL) are added sodium hydrogensulfate (9.4 mmol) and pyrrolidine (9.4 mmol). After stirring at room temperature for 0.5 h, to the suspension is added sodium cyanide (9.4 mmol), and the resulting mixture is stirred at room temperature for 15 h. The reaction mixture is diluted with sat. aq. NaHCO3, then extracted with AcOEt. The organic extracts are washed with water (×2) and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give phenylpyrrolidin-1-ylacetonitrile, which is directly used for the next reaction without further purification.
Reaction SMILES: [N:1]1([C:7]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:9][CH2:10]2)[CH2:6][CH2:5]1)(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCOC(=O)C1(N2CCNCC2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(N2CCN(S(=O)(=O)c3ccccc3Cl)CC2)CCC1

Procedure:
Ethyl 1-(piperazin-1-yl)cyclobutanecarboxylate (0.71 mmol) was dissolved in CH2Cl2 (5 ml). Triethylamine (0.30 ml, 2.1 mmol), followed by 2-chlorobenzenesulfonyl chloride (0.11 ml, 0.79 mmol), was added at room temperature. The orange-colored solution was stirred at room temperature for 6 h before saturated NaHCO3 solution was added. The mixture was extracted twice with EtOAc. Combined organic layers were washed once with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, gradient 5-10% Et2O/CH2Cl2) to give ethyl 1-(4-(2-chlorophenylsulfonyl)piperazin-1-yl)cyclobutanecarboxylate as a colorless oil.
Reaction SMILES: [K].[K].[C:3]12([C:13]3[CH:18]=[C:17]([C:19]45[CH2:28][CH:23]6[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]6)[CH2:20]4)[CH2:26]5)[C:16]([O:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32][CH:31]=4)=[CH:15][C:14]=3[O:39][C:40]3[CH:45]=[CH:44][C:43]([C:46]([OH:48])=[O:47])=[CH:42][CH:41]=3)[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[Cl:49]CCCl.S(Cl)([Cl:55])=O.C1(C=CC(O)=CC=1)O>CN(C)C=O>[Cl-:49].[Cl-:55].[C:3]12([C:13]3[CH:18]=[C:17]([C:19]45[CH2:20][CH:21]6[CH2:27][CH:25]([CH2:24][CH:23]([CH2:22]6)[CH2:28]4)[CH2:26]5)[C:16]([O:29][C:30]4[CH:31]=[CH:32][C:33]([C:36]([OH:38])=[O:37])=[CH:34][CH:35]=4)=[CH:15][C:14]=3[O:39][C:40]3[CH:45]=[CH:44][C:43]([C:46]([OH:48])=[O:47])=[CH:42][CH:41]=3)[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2
Reactant: O=S(Cl)Cl
Reactant: ClCCCl
Agent: O=C(O)c1ccc(Oc2cc(Oc3ccc(C(=O)O)cc3)c(C34CC5CC(CC(C5)C3)C4)cc2C23CC4CC(CC(C4)C2)C3)cc1
Agent: Oc1ccc(O)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: [Cl-]

Procedure:
Next, 62.5 g of the 4,6-di(1-adamantyl)-1,3-bis(4-carboxy-phenoxy)benzene dipotassium salt obtained above (90 mmol), 200 mL of 1,2-dichloroethane and a stirrer were charged in a 2 L recovery flask. Then, 178.5 g of thionyl chloride mol) was gradually added thereto with agitating at 5° C. or less. After the addition, 1.5 mL of N,N-dimethylformamide and 1.5 g of hydroquinone were added and agitated at 45 to 50° C. for three hours. After reaction solution was filtered, solvent was removed from the reaction solution under reduced pressure. Solid thus obtained was washed with hexane and then recrystallized with diethyl ether, thus obtaining 38.9 g of 4,6-di(1-adamantyl)-1,3-bis(4-carboxy-phenoxy)benzene-dichloride (59.4 mmol; yield: 66.0%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[C:11]([OH:15])([CH3:14])[CH2:12][OH:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[C:11]([OH:15])([CH3:14])[CH2:12][O:13][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:5][C:4]=1[C:17]([F:19])([F:18])[F:20])#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)(CO)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(O)(COS(C)(=O)=O)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 46 g (0.16 mol) of N-[4-cyano-3-trifluoromethyl-phenyl]-2,3-dihydroxy-2-methyl-propionamide in 1 1 of dichloromethane and 46 ml (0.57 mol) of dry pyridine was cooled to 0° C. and 46 ml (0.59 mol) of methanesulfonyl chloride was added dropwise. The mixture was stirred at 0° C. for 5 h, then washed three times with 500 ml of saturated aqueous sodium hydrogen carbonate, 500 ml of 10% aqueous hydrochloric acid and 500 ml of brine. The organic layer was dried over sodium sulfate and concentrated in vacuum. The residue was crystallized with 200 ml of petroleum ether, which has a boiling range of 40–70° C.
Reaction SMILES: CC1C=C(C(C)(C)C)C=C(C)C=1S(F)(F)[F:14].[CH:17]1[CH:22]=[CH:21][C:20]([C@@H:23](O)[C@@H:24](O)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=C[CH:18]=1.FC(C1C=CC=CC=1)[CH:35]([F:42])C1C=CC=CC=1>C(Cl)Cl>[F:14][CH:35]([F:42])[CH:24]([C:23]1[CH:18]=[CH:17][CH:22]=[CH:21][CH:20]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cc(C(C)(C)C)cc(C)c1S(F)(F)F
Reactant: O[C@H](c1ccccc1)[C@@H](O)c1ccccc1
Reactant: FC(c1ccccc1)C(F)c1ccccc1
Solvent: ClCCl
Product: FC(F)C(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 0.03 %

Procedure:
In a 15 mL fluoropolymer flask, 2,6-dimethyl-4-tert-butylphenylsulfur trifluoride (0.625 g, 2.5 mmol) was dissolved in 5 mL of anhydrous CH2Cl2. A solution of meso-1,2-diphenyl-1,2-ethanediol (0.214 g, 1.0 mmol) in 5 mL of anhydrous CH2Cl2 was added to the above stirred solution at room temperature. After 3 hours, C12H26F was added as standard, the 19F NMR analysis showed that 1,2-difluoro-1,2-diphenylethane (PhCHFCHFPh) was produced in 97% yield and a trace (˜0.03%) of 1,1-difluoro-2,2-diphenylethane (Ph2CHCF2H) was formed. Products were characterized by comparing to the spectroscopic data in literature (see Journal of Fluorine Chem. Vol. 125, pp 1869-1872 (2004)).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7](S(C)(=O)=O)[N:6]=[C:5]([C:13]([OH:15])=[O:14])[CH:4]=1)[CH3:2].[CH2:16]([NH2:18])[CH3:17]>C1COCC1.O>[CH2:1]([C:3]1[N:8]=[C:7]([NH:18][CH2:16][CH3:17])[N:6]=[C:5]([C:13]([OH:15])=[O:14])[CH:4]=1)[CH3:2]
Reactant: CCc1cc(C(=O)O)nc(S(C)(=O)=O)n1
Reactant: CCN
Solvent: C1CCOC1
Solvent: O
Product: CCNc1nc(CC)cc(C(=O)O)n1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 6-ethyl-2-methanesulfonyl-pyrimidine-4-carboxylic acid (325 mg, 1.41 mmol) in THF (5 mL) is added 70% ethylamine in water (2.0 mL). The mixture is stirred at 70° C. overnight. It is then evaporated to dryness and purified by prep. TLC (DCM/7N NH3 in MeOH 4/1) to give 6-ethyl-2-ethylamino-pyrimidine-4-carboxylic acid as a yellow oil (200 mg); LC-MS: tR=0.58 min, [M+H]+=194.07. 1H NMR (CDCl3): δ 1.34 (m, 6H), 2.84 (d, J=7.5 Hz, 2H), 3.64 (m, 2H), 7.26 (s, 1H), 11.0 (s br, 1H).
Reaction SMILES: C([Li])(C)(C)C.[OH:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:29]1([CH2:35][C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCCCC.O1CCCC1>[C:29]1([CH2:35][C:36]([O:6][CH:7]([C:20]2[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCCCCCCCCC(OC(=O)Cc1ccccc1)c1coc([Si](C)(C)C)c1
Reaction time: 0.42 h

Procedure:
tert-Butyl lithium (a 1.7M solution in pentane; 0.29 ml, 0.49 mmol) was added dropwise to a solution of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (138.2 mg, 0.41 mmol) in tetrahydrofuran (7 ml) at -78 degrees under argon. After 25 minutes, a solution of phenylacetyl chloride (65 microliter, 0.49 mmol) in tetrahydrofuran (1/2 ml) was added. Stirring was continued at room temperature for 16 hours and quenched with water. Extraction (ethyl ether) and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was purified by preparative TLC (20×20 cm, 500 micron silica plate; developed with 10% ethyl ether/hexane). The title ester was obtained as a pale yellow oil.