Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[NH2:20])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:22]=[C:23](Cl)OC(Cl)(Cl)Cl.[N-]=C=O.Cl.[CH3:34][O:35][C:36](=[O:57])[C@@H:37]([NH2:56])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46](=[O:55])[C:47]2[C:52]([Cl:53])=[CH:51][CH:50]=[CH:49][C:48]=2[Cl:54])=[CH:41][CH:40]=1.C(N(CC)CC)C>O1CCOCC1.ClCCl>[CH3:34][O:35][C:36](=[O:57])[C@@H:37]([NH:56][C:23]([NH:20][C:11]1[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:21])=[CH:6][CH:5]=1)(=[O:9])=[O:8])=[O:22])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46](=[O:55])[C:47]2[C:48]([Cl:54])=[CH:49][CH:50]=[CH:51][C:52]=2[Cl:53])=[CH:41][CH:40]=1
Reactant: Cc1ccc(S(=O)(=O)c2ccc(C(F)(F)F)cc2N)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: Cl
Agent: [N-]=C=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)Nc1cc(C(F)(F)F)ccc1S(=O)(=O)c1ccc(C)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 163.9 %

Procedure:
A mixture of 2-(toluene-4-sulfonyl)-5-trifluoromethylphenylamine (0.2 g, 0.63 mmol) and diphosgene (0.061 g, 0.31 mmol) in dioxane (2 ml) was heated at 60° C. for 16 h. The solvent was removed under reduced pressure. The crude isocyanate was slowly added to a solution of (S)-2-amino-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester hydrochloride (0.25 g, 0.63 mmol) and triethylamine (0.063 g, 0.63 mmol) in dichloromethane (2 ml) and the resulting reaction mixture was stirred at room temperature overnight. The precipitate obtained was collected by filtration, washed several times with dichloromethane and dried under vacuum to yield the title compound (0.36 g, 82%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:10]([OH:12])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:32]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44]CCC(C)C)[CH:39]=1)[CH2:33][CH:34]([CH3:36])[CH3:35]>C(Cl)Cl.O.CN(C)C=O>[OH:44][C:40]1[CH:39]=[C:38]([O:37][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:43]=[CH:42][C:41]=1[C:10]([C:9]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])[CH:8]=1)=[O:12]
Reactant: CCOC(=O)CCc1cc(C(=O)O)ccc1OCC(C)C
Reactant: CC(C)CCOc1cccc(OCCC(C)C)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cc(C(=O)c2ccc(OCCC(C)C)cc2O)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
In 10 ml of methylene chloride is dissolved 1.00 g of 3-(3-ethoxy-3-oxopropyl)-4-isobutoxybenzoic acid. After adding 0.36 ml of oxalyl chloride and 20 μl of N,N-dimethylformamide successively at ambient temperature, the mixture thus obtained is stirred at ambient temperature for one hour. Then, 0.95 g of aluminum chloride and 1.02 g of 1,3-diisopentyloxybenzene are successively added at 5-10° C., and stirred at the same temperature as above for 30 minutes and then at ambient temperature for 30 minutes. Then, 0.45 g of aluminum chloride is added at ambient temperature and stirred at the same temperature as above for 30 minutes. The reaction mixture is added to a mixture of methylene chloride and water, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=10:1) to obtain 0.63 g of ethyl 3-[5-(2-hydroxy-4-isopentyloxybenzoyl)-2-isobutoxyphenyl]propanoate as a light yellow oily product. A 0.60 g portion of the oily product obtained above is dissolved in 12 ml of ethanol, 1.3 ml of 5 mol/L sodium hydroxide solution is added, and the mixture thus obtained is stirred at ambient temperature for 2 hours. Chloroform and water are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Thus, 0.48 g of [5-(2-hydroxy-4-isopentyloxybenzoyl)-2-isobutoxyphenyl]-propanoic acid is obtained as a light yellow solid product.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([CH:8]=O)=[CH:5][CH:4]=1.Cl.[C:11]([O:15][C:16](=[O:20])[CH2:17][CH2:18][NH2:19])([CH3:14])([CH3:13])[CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([N:52]=[C:53]=[S:54])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1>C(Cl)Cl>[C:11]([O:15][C:16](=[O:20])[CH2:17][CH2:18][N:19]([CH2:8][C:6]1[S:7][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)[C:53]([NH2:52])=[S:54])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CSc1ccc(C=O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CSc1ccc(CN(CCC(=O)OC(C)(C)C)C(N)=S)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.6 %

Procedure:
A mixture of 5-methylsulfanyl-thiophene-2-carbaldehyde (1.0 g, 6.3 mmol) and 3-amino-propionic acid tert-butyl ester hydrochloride (1.02 g, 7 mmol) in DCM (20 mL) was stirred at RT for 15 min. Sodium triacetoxyborohydride (2 g, 9.45 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mass was partitioned between aqueous sodium bicarbonate and DCM. The organic layer was dried over sodium sulfate and concentrated to give the crude 3-[(5-methylsulfanyl-thiophen-2-ylmethyl)-amino]-propionic acid tert-butyl ester (800 mg, 38% yield). This crude amine (800 mg, 2.4 mmol) was dissolved in DCM (10 mL) and Fmoc-isothiocyanate (740 mg, 2.6 mmol) was added. After stirring the reaction overnight at room temperature, piperidine (3 mL) was added and the deprotection reaction was stirred for 30 min. The reaction mixture was concentrated and purified using a silica gel column. Concentration of the appropriate fractions under vacuum gave the desired thiourea (600 mg, 63% yield). This material is unstable and should be kept in the cold to prevent decomposition by cyclization and loss of t-BuOH. LC-MS m/z: 347 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 6.85 (d, 1H), 6.82 (d, 1H), 5.85 (s, 2H), 3.52 (t, 2H), 2.65 (t, 2H), 2.41 (s, 3H), 2.38 (s, 3H), 1.38 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Temperature: -5 °C

Procedure:
3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester is dissolved in dry pyridine (20 ml) and cooled to −5° C. Methanesulphonyl chloride is added over a period of 10 minutes keeping the temperature between −5° C. and 0° C. after which the yellow solution is allowed to warm up to room temperature over a period of 30 minutes. Water (20 ml) is added and the mixture is then extracted using DCM (2×30 ml), the organic washings being combined and washed with 2N potassium hydrogen sulphate solution (2×30 ml). The organic phase is dried (using MgSO4), filtered and evaporated to give the title compound as a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH2:26][NH2:27])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH2:26][NH2:27])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH2:10][CH2:11]1)=[O:5])[CH3:2].[CH:4]([OH:5])=[O:3].[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH2:26][NH:27][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([Cl:28])=[CH:30][CH:31]=3)=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=Cc1ccc(Cl)cc1
Agent: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(CN)c3ccccc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(CNCc3ccc(Cl)cc3)c3ccccc23)CC1
Product: O=CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(4-Aminomethyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester (32) was prepared according to the procedure in Scheme 12. To a 25° C. solution of 4-(4-aminomethyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester (32) (62 mg, 0.159 mmol) in MeOH (4 mL) was added 4-chloro-benzaldehyde (45 mg, 0.318 mmol) and sodium cyanoborohydride (50 mg, 0.795 mmol). After stirring for 2 h at 25° C., the solution was concentrated in vacuo to give a solid. The resultant solid was purified by reverse phase HPLC providing 4-{4-[(4-chloro-benzylamino)-methyl]-naphthalene-1-sulfonylamino}-piperidine-1-carboxylic acid ethyl ester formate salt (G-7). 1H NMR (300 MHz, MeOD) δ 8.76 (m, 1H), 8.38 (s, br, 1H), 8.24 (d, 1H), 8.18 (m, 1H), 7.51 (m, 3H), 7.44 (m, 4H), 4.52 (s, 2H), 4.12 (s, 2H), 4.04 (q, 2H), 3.60 (d, 2H), 3.40 (m, 1H), 2.72 (m, 2H), 1.50 (m, 2H), 1.25 (m, 2H), 1.18 (t, 3H); LC/MS m/z 516 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].F[C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=1[F:34]>CCOC(C)=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=2[F:34])[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2ccc(OCc3ccccc3)cc2=O)c(F)c1
Reaction time: 0.08 h
Yield: 803.4 %

Procedure:
To 4-(benzyloxy)pyridin-2(1H)-one (6.12 g, 30 4 mmol) in a 500 mL recovery flask was applied vacuum for 5 minutes then placed under an atmosphere of nitrogen and added DMF (100 mL) to produce a suspension. Added NaH (60% in oil) (1.271 g, 31.8 mmol) over 10 minutes as a slow evolution of gas was observed. By 60 minutes, the tan suspension had become thicker and lighter in color. After 60 minutes added 1,2-difluoro-4-(methylsulfonyl)benzene (5.31 g, 27 6 mmol) and placed the reaction mixture in a 110° C. oil bath under nitrogen for 70 minutes to produce a tan suspension. Added 400 mL of water and 400 mL of EtOAc to the reaction, removed aqueous layer, washed organic layer with 400 mL of brine, dried with MgSO4, filtered and concentrated to give 12 g pale yellow powder. This was purified by flash chromatography (0.75-1.00% MeOH/CH2Cl2) followed by recrystallization from EtOAc to yield 5.39 g (14 4 mmol, 52% yield) of product as a white powder. MS (ESI) 374.4 (M+1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][NH:8][C:9]([C:11]2[N:12]=[C:13]3[C@H:20]([NH:21]C(=O)OCC4C=CC=CC=4)[C@@:19]4([CH3:35])[C:32]([CH3:34])([CH3:33])[C@H:16]([CH2:17][CH2:18]4)[CH2:15][N:14]3[C:36](=[O:39])[C:37]=2[OH:38])=[O:10])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53].N(C)C>C(Cl)Cl.CO>[F:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][NH:8][C:9]([C:11]2[N:12]=[C:13]3[C@H:20]([NH:21][S:52]([CH3:51])(=[O:54])=[O:53])[C@@:19]4([CH3:35])[C:32]([CH3:34])([CH3:33])[C@H:16]([CH2:17][CH2:18]4)[CH2:15][N:14]3[C:36](=[O:39])[C:37]=2[OH:38])=[O:10])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)[C@@H](NC(=O)OCc1ccccc1)c1nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n1C2
Agent: CNC
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)[C@@H]2CC[C@@]1(C)[C@@H](NS(C)(=O)=O)c1nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n1C2
Reaction time: 4 h
Yield: 69.1 %

Procedure:
To a stirred solution of benzyl ((7S,10R,11R)-2-((4-fluorobenzyl)carbamoyl)-3-hydroxy-10,12,12-trimethyl-4-oxo-6,7,8,9,10,11-hexahydro-4H-7,10-methanopyrimido[1,2-a]azocin-11-yl)carbamate hydrochloride salt (0.025 g, 0.055 mmol) and diisopropyl-ethylamine (0.175 mL, 1 mmol) in CH2Cl2 (3 mL) was added methanesulfonyl chloride (0.039 mL, 0.5 mmol) at room temperature. After 4 h, 2M Me2NH in methanol (1 mL) was added and stirring continued at room temperature. After 16 h, the reaction mixture was concentrated and purified by preparative-HPLC using methanol/water (0.1% trifluoroacetic acid) to afford the title compound (0.0186 g, 0.038 mmol, 68% yield) as a purple solid after crystallization from methanol/water. 1H NMR (500 MHz, CDCl3) δ: 12.39 (1 H, s), 8.60 (1 H, brs), 7.34 (2 H, dd, J=8.5, 5.2 Hz), 7.01 (2 H, t, J=8.7 Hz), 6.07 (1 H, d, J=9.5 Hz), 5.19 (1 H, dd, J=15.6, 8.5 Hz), 4.79 (1 H, d, J=9.8 Hz), 4.52-4.65 (2 H, m), 3.63 (1 H, d, J=15.6 Hz), 2.76 (3 H, s), 2.10 (1 H, t, J=8.1 Hz), 1.80-1.89 (1 H, m), 1.43-1.51 (1 H, m), 1.30-1.35 (1 H, m), 1.29 (3H, s), 1.04 (3 H, s), 1.01 (3 H, s), 0.96-1.01 (1 H, m). LCMS (M+H) calcd for C23H30FN4O5S: 493.19; found: 493.24. Purity: >98%.
Reaction SMILES: [Br:1][C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.[O:12]=[S:13]1(=[O:27])[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([CH2:19][N:16]4[CH2:17][CH2:18][S:13](=[O:27])(=[O:12])[CH2:14][CH2:15]4)=[CH:21][CH:22]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Reactant: Oc1ncc2ccc(Br)n2n1
Product: O=S1(=O)CCN(Cc2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1

Procedure:
(7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(1,1-dioxo-1 $1(6)-thiomorpholin-4-ylmethyl)-phenyl]-amine was prepared from 7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 4-(1,1-dioxo-1$1(6)-thiomorpholin-4-ylmethyl)-phenylamine in an analogous manner to Example 1052a. Product isolated as a yellow foam (134 mg, 66%). LCMS (m/e) 301 (M—N(CH2)4SO2); 1H-NMR (CDCl3, 400 MHz) δ 8.60 (s, 1H), 7.73 (d, 2H, J=8.5 Hz), 7.31 (d, 2H, J=8.5 Hz), 6.92 (s, 1H), 6.81 (d, 1H, J=4.8 Hz), 6.76 (d, 1H, J=4.8 Hz), 3.63 (s, 2H), 3.10-3.03 (m, 4H), 3.03-2.97 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:12])=[CH:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH2:29][CH3:30])([CH3:28])[CH3:27])=[CH:22][C:21]=1[C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])=[O:14].[Cl:36][C:37]([Cl:42])([Cl:41])[C:38](Cl)=[O:39].C(N(CC)CC)C.C(#N)C>O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:38](=[O:39])[C:37]([Cl:42])([Cl:41])[Cl:36])=[CH:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH2:29][CH3:30])([CH3:27])[CH3:28])=[CH:22][C:21]=1[C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])=[O:14]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc(N)c3ccccc3c2O)c(C(C)(C)CC)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc(NC(=O)C(Cl)(Cl)Cl)c3ccccc3c2O)c(C(C)(C)CC)c1

Procedure:
14.3 g of 1-hydroxy-4-amino-N-[γ-(2,4-di-tert-amylphenoxy)propyl]-2-naphthamide obtained in Step (b) of Synthesis I, 6 g of trichloroacetyl chloride and 3.3 g of triethylamine were added to 300 ml of acetonitrile, and the mixture was refluxed for 4 hours. After conclusion of the reaction, the reaction solution was condensed to 100 ml and water was added thereto. The solution was then extracted with ethyl acetate. After removal of the ethyl acetate by distillation, n-hexane was added to the residue. The solid precipitate was separated by filtration and recrystallized from ethanol to obtain the object compound. Yield: 10 g. Melting point: 190° - 192° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])(=[O:5])[C:2]([CH3:4])=[CH2:3].COC1C=CC(O)=CC=1.[CH2:21]([Cl:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[Cl-:28].[C:1]([O:6][CH2:7][CH2:8][N+:9]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:11])[CH3:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCN(C)C
Reactant: ClCc1ccccc1
Agent: COc1ccc(O)cc1
Solvent: CC(C)=O
Product: C=C(C)C(=O)OCC[N+](C)(C)Cc1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into a two-necked flask provided with a reflux condenser and a dropping funnel were introduced 94.3 g (0.6 mol) of methacryloyloxyethyl-N,N-dimethylamine, 152 g of acetone and 0.1 g of hydroquinone monomethyl ether, which was employed as a polymerization inhibitor, and then mixed homogeneously. After dropping 75.9 g (0.6 mol) of benzyl chloride thereinto within about 15 minutes, the mixture was allowed to stand overnight under stirring at room temperature. Then the reaction mixture was washed with 500 ml of acetone to obtain crystals of methacryloyloxyethyl-N,N-dimethylbenzylammonium chloride.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:50]3[O:49][C:48]([NH2:51])=[N:47][C:46]=3[C:45]([O:52][CH3:53])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:51][C:48]2[O:49][C:50]3[C:42]([C:39]4[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=4)=[CH:43][CH:44]=[C:45]([O:52][CH3:53])[C:46]=3[N:47]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COc1ccc(-c2ccc(F)cc2)c2oc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(F)cc2)c2oc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
From 4-fluorobenzoic acid, HATU and N-diethylisopropylamine in THF, then treatment with 7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 381 (M+H+, 100).
Reaction SMILES: I.CS[C:4](=[NH:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:19][O:20][CH2:21][CH2:22][NH2:23].C(O)C.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>CO>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[CH3:19][O:20][CH2:21][CH2:22][NH:23][C:4]([NH2:18])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:19][O:20][CH2:21][CH2:22][NH:23][C:4]([NH2:18])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CSC(=N)Nc1ccccc1N1CCCCC1
Reactant: COCCN
Agent: I
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Product: COCCNC(N)=Nc1ccccc1N1CCCCC1

Procedure:
A mixture of 2-methyl-1-(2-piperidino)phenyl]-2-thiopseudourea hydroiodide (7.5 g prepared as described in Preparative Procedure G), 2-methoxyethylamine (2 ml) and ethanol (40 ml was stirred at ambient residue which was dissolved in methanol and treated with fumaric acid to give 1-(2-methoxyethyl)-2-(2-piperidinophenyl)guanidine hemifumarate (m.p. 218°-220° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: ClC1C(Cl)=C(C2C=CC(Cl)=CC=2)N=C(C(Cl)=O)C=1.[F-].[K+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:33]=[C:32]([C:34](F)=[O:35])[CH:31]=[C:30]([F:37])[C:29]=2[F:38])=[CH:24][CH:23]=1.C(N(CC)CC)C.[CH:46]([OH:49])([CH3:48])[CH3:47]>S1(CCCC1)(=O)=O.O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:33]=[C:32]([C:34]([O:49][CH:46]([CH3:48])[CH3:47])=[O:35])[CH:31]=[C:30]([F:37])[C:29]=2[F:38])=[CH:24][CH:23]=1
Reactant: O=C(F)c1cc(F)c(F)c(-c2ccc(Cl)cc2)n1
Reactant: CC(C)O
Agent: O=C(Cl)c1cc(Cl)c(Cl)c(-c2ccc(Cl)cc2)n1
Agent: [F-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: CC(C)OC(=O)c1cc(F)c(F)c(-c2ccc(Cl)cc2)n1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 48 %

Procedure:
To a solution of 4,5-dichloro-6-(4-chlorophenyl)picolinoyl chloride (2.0 g, 6.23 mmol) in sulfolane (40 mL, dried over 4 Å molecular sieves, 100 ppm H2O) was added potassium fluoride (2.2 g, 37.4 mmol). The reaction mixture was heated at 130° C. for 24 h. Reaction mixture was analyzed by GC-MS and 19F NMR. Data for 6-(4-chlorophenyl)-4,5-difluoropicolinoyl fluoride, GC-MS: m/z=271, 223; 19F NMR (376 MHz, Toluene-d8) δ 17.05 (s), −123.81 (d, J=19.1 Hz), −140.17 (d, J=19.1 Hz). Reaction was allowed to cool to room temperature and triethylamine (1.1 mL, 7.8 mmol) and isopropanol (0.7 mL, 9.4 mmol) were added. After stirring for 1.5 h, the reaction mixture was diluted with water (100 mL) and transferred to a reparatory funnel. The reaction mixture was extracted with methyl tert-butyl ether (MTBE, 2×50 mL). The combined organic extracts were washed with water (3×50 mL) and saturated NaCl (50 mL) and concentrated under reduced pressure to provide a brown oil. The crude product oil was purified by silica gel flash chromatography (hexane/ethyl acetate gradient, 100% hexane→20% hexane/ethyl acetate) to provide 0.93 g (48% yield) of isopropyl 6-(4-chlorophenyl)-4,5-difluoropicolinate as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.04-7.98 (m, 2H), 7.90 (dd, J=9.4, 5.3 Hz, 1H), 7.51-7.45 (m, 2H), 5.31 (hept, J=6.3 Hz, 1H), 1.43 (d, J=6.3 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 162.72 (d, J=3.5 Hz), 158.12 (d, J=12.6 Hz), 155.49 (d, J=12.4 Hz), 149.41 (d, J=11.0 Hz), 147.16 (dd, J=7.9, 1.0 Hz), 146.73 (d, J=10.9 Hz), 136.51 (d, J=0.9 Hz), 130.34 (d, J=6.6 Hz), 128.93 (s), 113.80 (d, J=16.1 Hz), 70.25 (s), 21.85 (s); 19F NMR (376 MHz, CDCl3) δ −124.73 (dd, J=17.7, 9.5 Hz), −144.38 (dd, J=17.7, 5.4 Hz); MS Calcd. for C16H15F2NO3: 307.10. Found: 307 (M+), 221, 206; mp=73-74° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:12]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:12]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:26][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)C(c1cccc(Cl)c1)C1(O)CCCCC1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)C(c1cccc(Cl)c1)C1(O)CCCCC1

Procedure:
In an analogous manner to Example 1, step 1 2-(3-chlorophenyl-2-(1-hydroxycyclohexyl)-N-[4-(trifluoromethyl)benzyl]acetamide was prepared from (3-chlorophenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-a) and 4-trifluoromethylbenzylamine. MS (ESI) m/z 426/428 ([M+H]+).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[C:4]#[N:5].O[NH2:8].[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([C:13]2[O:14][N:8]=[C:4]([CH:3]([OH:6])[CH2:2][CH3:1])[N:5]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: NO
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCC(O)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCC(O)c1noc(-c2cccc(Cl)c2)n1
Reaction time: 3 h
Yield: 44 %

Procedure:
Propionaldehyde cyanohydrin (9.62 g, 113 mmol) was added slowly to hydroxyl amine (100 ml, 1.27 M in EtOH) at 0° C. Stirring was continued at r.t. for 3 h and then the reaction mixture was concentrated to dryness under reduced pressure to give crude (E/Z)-N′,2-dihydroxybutanimidamide (9.1 g, 68%). Crude (E/Z)-N′,2-dihydroxybutanimidamide (8.0 g, 67.7 mmol) was dissolved in pyridine (350 ml) and 3-chlorobenzoyl chloride (8.72 ml, 67.7 mmol) was added slowly at 0° C. After stirring at r.t. for 1 h the mixture was heated at reflux o.n. After cooling to r.t. sat. aq. NaHCO3 was added and the mixture was extracted with DCM. The organic phase was washed with water and brine, dried and concentrated. Column chromatography (hep/EA 4:1) gave 7.15 g (44%) of the title compound. 1H NMR: 1.04 (t, 3 H) 2.00 (m, 2 H) 2.35 (m, 1 H) 4.87 (m, 1 H) 7.47 (t, 1 H) 7.57 (m, 1 H) 8.02 (m, 1 H) 8.14 (m, 1 H)