Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:16])([S:14][CH3:15])[O:2][O:3][CH:4]([O:8][C:9](=[O:13])[CH:10]([CH3:12])C)[CH:5]([CH3:7])[CH3:6].[C:17](O)(=O)CCC>>[C:1](=[O:16])([S:14][CH3:15])[O:2][O:3][CH:4]([O:8][C:9](=[O:13])[CH2:10][CH2:12][CH3:17])[CH:5]([CH3:6])[CH3:7]
Reactant: CSC(=O)OOC(OC(=O)C(C)C)C(C)C
Reactant: CCCC(=O)O
Product: CCCC(=O)OC(OOC(=O)SC)C(C)C

Procedure:
Following the procedures for synthesizing O-(1-isobutanoyloxyisobutoxy) S-methyl thiocarbonate (11) and replacing isobutyric acid with n-butyric acid affords O-(1-butanoyloxyisobutoxy) S-methyl thiocarbonate (14) as an oil.
Reaction SMILES: [S-]C#N.[K+].ClC1C=CC(N)=CC=1.BrBr.NC1[S:17][C:18]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=2[N:20]=1.[OH-].[K+]>C(O)(=O)C.O>[Cl:25][C:23]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([SH:17])[CH:24]=1
Reactant: Nc1nc2ccc(Cl)cc2s1
Agent: BrBr
Agent: N#C[S-]
Agent: Nc1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(Cl)cc1S
Reaction time: 0.5 h

Procedure:
Potassium thiocyanate (38.8 g, 0.40 mole) and 4-chloroaniline (50.9 g, 0.40 mole) are dissolved in 300 mL of glacial acetic acid. The solution is cooled below 10° C. in an ice bath and while stirring, bromine (10 mL, 0.40 mole) in glacial acetic acid (50 mL) is added dropwise over one hour with the temperature maintained below 10° C. with external cooling. Stirring is continued for an additional 30 minutes. The reaction mixture is stirred at room temperature for 16 hours. The hydrobromide salt of 2-amino-6-chlorobenzothiazole 5 (X=Cl) is washed with hexane (2×25 mL). The salt is dissolved in warm water (300 mL) and the product precipitated by addition of dilute (10%) sodium hydroxide. The crude product is filtered and recrystallized from ethanol (mp 198-200° C., yield 16.47 g, 63.3%). A mixture of 2-amino-6-chlorobenzothiazole 5 (15 g, 0.08 mole), potassium hydroxide (75 g, 1.34 mole), and water (150 mL) is heated with stirring under reflux over nitrogen for 8 hours. The vigorous reaction subsides slowly. The mixture is then diluted with water (20 mL) and filtered. To the filtrate is added 5 N acetic acid with vigorous stirring and cooling until it is just acid to pH paper. The yellow crystals are filtered, washed with cold water and recrystallized from absolute ethanol and decolorized with neutral Norit. Yield of 5-chloro-2-aminobenenethiol (6, X=Cl); 40%; mp 108-110° C. (lit 110° C.).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].I[CH2:15][CH2:16][C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21].O>O1CCCC1>[F:28][C:17]([F:29])([C:18]([F:26])([F:27])[C:19]([F:24])([F:25])[C:20]([F:21])([F:23])[F:22])[CH2:16][CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
Anhydrous tetrahydrofuran (200 ml) was added to 60% sodium hydride (2.78 g, 69.52 mmol) and the resulting mixture was cooled to 0° C. Diethyl malonate (12.18 ml, 80.22 mmol) was slowly added dropwise to this mixture, which was then stirred for 1 hour at room temperature. A solution of 1-iodo-3,3,4,4,5,5,6,6,6-nonafluorohexane (20.0 g, 53.48 mmol) in anhydrous tetrahydrofuran (50 ml) was then slowly added dropwise to the mixture, followed by stirring for 12 hours at room temperature. Water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/50) to give diethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)malonate (19.4 g, Yield 89%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1)=[O:6].[C:17]([NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>>[C:17]([NH:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[O:6])[CH2:28][CH2:27]1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)c1ccc(C(=O)CCCN2CCC(NC(=O)c3ccccc3)CC2)cc1
Yield: 57.4 %

Procedure:
4-Chloro-4'-tert-butylbutyrophenone (3.58 g.), 4-benzamidopiperidine (3.06 g.) and anhydrous potassium carbonate 2.67 g.) were reacted together in the manner of Example 68 to give the title compound (3.495 g.) as the hydrochloride, colourless microcrystals, m.p. 268.0°. Analysis: Found: C, 70.50; H, 8.14; N, 6.29. C26H34N2O2.HCl requires C, 70.48; H, 7.96; N, 6.32%.
Reaction SMILES: [CH:1]1([C:6]2[N:11]=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=[O:21])=[CH:15][CH:14]=3)[CH:9]=[C:8]([C:23]([F:26])([F:25])[F:24])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)CCl.C1C=CC2N(O)N=[N:37]C=2C=1.N.CO>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([C:6]2[N:11]=[C:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:19][C:20]([NH2:37])=[O:21])=[CH:17][CH:18]=3)[CH:9]=[C:8]([C:23]([F:26])([F:24])[F:25])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)Cc1ccc(Cc2cc(C(F)(F)F)nc(C3CCCC3)n2)cc1
Reactant: On1nnc2ccccc21
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)Cc1ccc(Cc2cc(C(F)(F)F)nc(C3CCCC3)n2)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of 2-(4-((2-cyclopentyl-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetic acid (0.045 g, 0.12 mmol) in DMF (2 mL) was added EDC (0.047 g, 0.24 mmol), HOBT (0.033 g, 0.24 mmol) and 7N ammonia in methanol (0.17 mL, 1.2 mmol). The mixture was sealed and stirred at 85° C. for 3 h. After this time, the mixture was diluted with ethyl acetate and then washed with water. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.034 g, 79%) as a white solid. MW=363.38. 1H NMR (DMSO-d6, 500 MHz) δ 7.71 (s, 1H), 7.41 (s, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 6.83 (s, 1H), 4.16 (s, 2H), 3.41-3.33 (m, 1H), 3.33 (s, 2H), 2.09-1.99 (m, 2H), 1.89-1.61 (m, 6H); APCI MS m/z 364 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[NH:4][N:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:7]([C:6]1[C:2]([NH:1][C:22](=[O:24])[CH3:23])=[N:3][NH:4][C:5]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)#[N:8]
Reactant: N#Cc1c(N)n[nH]c1N1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1n[nH]c(N2CCN(Cc3ccccc3)CC2)c1C#N

Procedure:
A 2.82 g (0.01 mole) amount of 3-amino-5-(4-benzyl-1-piperazinyl)-4-pyrazolecarbonitrile (prepared as described in Example 8) was added to 50 ml of acetic anhydride with stirring. After nearly complete solution a heavy precipitate was formed. The mixture was stirred for 18 hours at room temperature beneath a drying tube containing a desicant.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([CH:29]=[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][N:23]=1)=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH2:33]([O:32][C:30]1[CH:29]=[C:18]([CH:17]=[C:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:31]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:24][N:23]=1)=[O:20])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Nc1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1
Reactant: CC(C)(C)N=C=O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)Nc1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.8 %

Procedure:
A solution of tert-butyl isocyanate (51 mg) in THF (5 ml) was treated with 2-[(3,5-dibenzyloxybenzoyl)amino]-5-aminopyridine (212 mg), and stirred at ambient temperature for 24 hours. More tert-butyl isocyanate (0.34 ml) added, and stirring continued at ambient temperature for a further 4 days. Volatile material was removed by evaporation and the residue was triturated under methanol to give the title compound (159 mg) as a solid, 1H NMR δ (d6-DMSO): 1.30 (s, 9H), 5.18 (s, 4H), 6.09 (s, 1H), 6.85 (s, 1H), 7.32 to 7.50 (m, 12H), 7.78 (dd, 1H), 8.04 (d, 1H), 8.38 (s, 1H), 8.44 (s, 1H), 10.65 (s, 1H). MS ES+ 525.61 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:8]1[N:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1>>[N+:14]([C:11]1[CH:10]=[N:9][C:8]([N:4]2[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]2)=[N:13][CH:12]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: O[C@H]1CCNC1
Product: O=[N+]([O-])c1cnc(N2CC[C@H](O)C2)nc1

Procedure:
This compound was prepared with the same method described before using (S)-3-hydroxypyrrolidine and 2-chloro-5-nitro-pyrimidine to give (S)—N-(5-nitropyrimidin-2-yl)-pyrrolidin-3-ol. LCMS calcd for C8H10N4O3 m/e 210.19, obsd 211 (ES, M+H). Hydrogenation of the nitro compound, as above, provided (S)—N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[O:15]=[C:16]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH:18]([C:27](O)=[O:28])[CH2:17]1>>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:27]([CH:18]1[CH2:17][C:16](=[O:15])[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19]1)=[O:28])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Reactant: O=C(O)C1CC(=O)N(c2ccccc2)C1
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1CC(=O)N(c2ccccc2)C1

Procedure:
The product from Example 92B and 5-oxo-1-phenylpyrrolidine-3-carboxylic acid (Princeton Bio) were processed using the method described in Example 92C to afford the title compound. 1H NMR (DMSO-d6) δ 0.91 (t, J=7.3 Hz, 3H), 1.26-1.38 (m, 2H), 1.58-1.66 (m, 2H), 1.61 (s, 9H), 2.64-2.69 (m, 2H), 2.85-2.89 (m, 2H), 3.49-3.58 (m, 1H), 4.12 (s, 1H), 4.14 (d, J=1.7 Hz, 1H), 7.08-7.14 (m, 1H), 7.31-7.38 (m, 2H), 7.62-7.68 (m, 2H), 8.48 (s, 1H). (ESI+) m/z 400 (M+H)+.
Reaction SMILES: ClC1C=C(C=C(C)C=1O)N.[Cl:11][C:12]1[C:20]([OH:21])=[C:19]([CH3:22])[CH:18]=[C:17]2[C:13]=1[C:14](=[O:24])[C:15](=[O:23])[NH:16]2.[CH:25]1[C:30]([NH:31][NH2:32])=[CH:29][CH:28]=[C:27]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:26]=1.Cl>>[Cl:11][C:12]1[C:20]([OH:21])=[C:19]([CH3:22])[CH:18]=[C:17]2[C:13]=1[C:14](=[O:24])[C:15](=[O:23])[NH:16]2.[Cl:11][C:12]1[C:20]([OH:21])=[C:19]([CH3:22])[CH:18]=[C:17]2[C:13]=1[C:14](=[N:32][NH:31][C:30]1[CH:29]=[CH:28][C:27]([S:33]([NH2:36])(=[O:34])=[O:35])=[CH:26][CH:25]=1)[C:15](=[O:23])[NH:16]2
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cc1cc(N)cc(Cl)c1O
Agent: Cc1cc2c(c(Cl)c1O)C(=O)C(=O)N2
Agent: Cl
Product: Cc1cc2c(c(Cl)c1O)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
4-Chloro-5-hydroxy-6-methyl-1H-indole-2,3-dione was prepared from 3-chloro-4-hydroxy-5-methyl aniline according to Procedure A and employing flash chromatography (hexanes:EtOAc 1:1) to isolate the desired isomer: 1H NMR (DMSO-d6): δ 2.35 (s, 3H), 6.67 (s, 1H), 9.17 (s, 1H), 10.81 (s, 1H); APCI-MS: m/z 210 (M−H)−. Anal. Calcd for C9H6NO3Cl: C, 51.08; H, 2.85; N, 6.62; Cl, 16.75. Found: C, 51.20; H, 2.90; N, 6.67; Cl, 16.85. The title compound was prepared from 4-chloro-5-hydroxy-6-methyl-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 95% yield: mp>250° C.; 1H NMR (DMSO-d6): δ 2.26 (s, 3H), 6.69 (s, 1H), 7.28 (s, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.82 (d, J=8.8 Hz, 2H), 8.84 (s, 1H), 11.02 (s, 1H), 13.00 (s, 1H); APCI-MS: m/z 379 (M−H)−. Anal. Calcd for C15H13N4O4CIS: C, 47.31; H, 3.44; N, 14.71; Cl, 9.31; S, 8.42. Found: C, 47.20; H, 3.47; N, 14.64; Cl, 9.41; S, 8.32.
Reaction SMILES: [CH3:1][C:2]1[N:3]2[C:7](=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:9]=1)[CH2:6][CH2:5][CH2:4]2.[F:16][C:17]([F:28])([C:24]([F:27])([F:26])[F:25])[C:18]([F:23])([F:22])[C:19](Cl)=[O:20].[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>ClC(Cl)C.C(Cl)Cl>[F:25][C:24]([F:26])([F:27])[C:17]([F:16])([F:28])[C:18]([F:22])([F:23])[C:19]([C:9]1[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:7]2[N:3]([C:2]=1[CH3:1])[CH2:4][CH2:5][CH2:6]2)=[O:20]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Cc1cc(-c2ccccc2)c2n1CCC2
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: Cc1c(C(=O)C(F)(F)C(F)(F)C(F)(F)F)c(-c2ccccc2)c2n1CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Methyl-7-phenyl-2,3-dihydro-1H-pyrrolizine (Example 30 c, 1.0 g, 0.005 mol), dissolved in dichloroethane (20 ml) is treated with heptafluorobutyryl chloride (0.83 ml, 1.3 g, 0.0055 mol) at RT and finally tin tetrachloride (0.7 ml, 1,56 g, 0.006 mol) in dichloroethane (5 ml) is added dropwise. The mixture warms to 35° C. and is stirred at RT for 16 h. The GC-MS analysis shows a 60% reaction. The reaction mixture is rendered alkaline with NaOH (25%, 25 ml) in an ice bath and, after addition of CH2Cl2 (25 ml), the organic phase is separated in a separating funnel. The alkali phase is extracted a further two times with dichloromethane (2×20 ml). These CH2Cl2 extracts are combined, dried over Na2SO4 sicc. and evaporated to dryness in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([N:15]([CH3:24])[C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:25]([N:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1)(=[O:27])[CH3:26]>>[C:25]([N:28]1[CH2:29][CH2:30][CH:31]([C:34]([N:11]2[CH2:12][CH2:13][C@@H:14]([N:15]([CH3:24])[C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10]2)=[O:35])[CH2:32][CH2:33]1)(=[O:27])[CH3:26]
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: CN(C(=O)c1ccccc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3ccccc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 14 and 1-acetylpiperidine-4-carboxylic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]3[N:15]([CH3:16])[C:14]4[CH:17]=[CH:18][C:19]([C:21](O)=[O:22])=[CH:20][C:13]=4[N:12]=3)=[N:7][C:6]=2[CH:24]=1.CN.[CH3:27][N:28](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:27][NH:28][C:21]([C:19]1[CH:18]=[CH:17][C:14]2[N:15]([CH3:16])[C:11]([NH:10][C:8]3[S:9][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:24][C:6]=4[N:7]=3)=[N:12][C:13]=2[CH:20]=1)=[O:22]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1c(Nc2nc3cc(F)ccc3s2)nc2cc(C(=O)O)ccc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3cc(F)ccc3s1)n2C
Yield: 68 %

Procedure:
2-(5-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid methylamide (24 mg) was prepared by following General Procedure F using 2-(5-fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (34 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 357.
Reaction SMILES: Cl.[NH:2]1[CH2:13][S:12][CH2:11][C@H:3]1[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].C(N(CC)CC)C.[CH2:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH:22]1[CH2:30][CH2:31][C:32](O)=[O:33].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21][CH:22]1[CH2:30][CH2:31][C:32]([CH:11]1[S:12][CH2:13][NH:2][C@@H:3]1[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])=[O:33]
Reactant: O=C(O)CCC1Cc2ccccc2C1
Reactant: O=C([C@@H]1CSCN1)N1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCC1Cc2ccccc2C1)C1SCN[C@@H]1C(=O)N1CCCC1
Reaction time: 0.17 h
Yield: 71.2 %

Procedure:
0.89 g of 1-L-thioprolylpyrrolidine hydrochloride was suspended in 20 ml of methylene chloride. To the suspension were added 0.40 g of triethylamine and 0.76 g of 3-(indan-2-yl)propionic acid under ice-cooling with stirring. After 10 minutes, 0.92 g of WSC.HCl was added to the mixture under ice-cooling while stirring. The mixture was sirred for 16 hours at room temperature. The reaction mixture was washed with diluted hydrochloric acid, water, and saturated sodium hydrogen carbonate in this order. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was recrystallized from ethyl acetate/isopropyl ether to produce 1.02 g of 1-{3-[3-(indan-2-yl)proprionyl]-L-thioprolyl]pyrrolidine as colorless crystals (yield: 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[CH:24]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20]C)=[O:19])[CH:13]=1)=[O:10].[OH-].[Na+].Cl>C1COCC1.CO.O>[Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[CH:24]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=1)=[O:10]
Reactant: COC(=O)c1cccc(NC(=O)c2cc(OCc3ccccc3Cl)cc(OCc3ccccc3Cl)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(NC(=O)c2cc(OCc3ccccc3Cl)cc(OCc3ccccc3Cl)c2)c1
Temperature: 25 °C

Procedure:
A suspension of methyl [3,5-di-(2-chlorobenzyloxy)benzoyl]aminobenzene-3-carboxylate (455 mg, 1.04 mmol) in THF was treated with sodium hydroxide solution (0.85 ml of 2M, 1.7 mmol), and the reaction stirred at ambient temperature, with tlc monitoring. Methanol (3 drops) and further additions of sodium hydroxide solution (2×0.85 ml of 2M, 3.4 mmol) were made, until complete hydrolysis was achieved. The resulting solution was diluted with water (30 ml) and acidified to pH1 (2M HCl); the precipitate thus formed was filtered off, washed (water) and dried to give the title compound as a colourless solid, 328 mg, 1H NMR δ (d6-DMSO): 5.25 (4H, s); 7.0 (1H, s); 7.4 (6H, m); 7.5 (2H, m); 7.6 (2H, m); 8.2 (1H, d).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[SH:14])[C:7]([O:9][CH3:10])=[O:8].Br[CH2:16][C:17]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]2([CH3:32])[CH3:31])=[CH2:18].Cl>CN(C=O)C.C(OCC)C>[I:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[S:14][CH2:18][C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1)=[CH2:16])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(S)c(I)c1
Reactant: C=C(CBr)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C(CSc1ccc(C(=O)OC)cc1I)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 0.33 h

Procedure:
75% NaH (115 mg, 3.58 mmol) is added to a solution of methyl 3-Iodo-4-mercaptobenzoate (531 mg, 3.25 mmol) in DMF (20 ml) at 0° C. Stirring is continued for 20 min at ambient temperature, then a solution of 6-(1-bromomethylvinyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (1 g, 3.25 mmol) in DMF (5 ml) is added dropwise. The mixture is stirred for 2 h at ambient temperature, and treated with an aqueous hydrochloric acid solution and ethyl ether. The organic phase is washed twice with water, dried over magnesium sulphate, and concentrated in vacuo at 40° C. in a rotary evaporator. The product is purified by flash chromatography on a silica column (CH2Cl2 50% heptane 50%).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:18][P:19]([N:30]([CH3:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([N:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:22])=[S:20])[CH2:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:8])=O>O1CCCC1.O>[CH3:38][N:30]([P:19]([CH2:18][NH:5][CH2:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:8])([N:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:22])=[S:20])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCCCCCCCOC(=O)CN(CP(=S)(N(C)Cc1ccccc1)N(C)Cc1ccccc1)C(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCOC(=O)CNCP(=S)(N(C)Cc1ccccc1)N(C)Cc1ccccc1
Temperature: 0 °C
Yield: 22.5 %

Procedure:
N-trifluoroacetyl-N-[bis(N-methyl-N-benzylamino)phosphinothioylmethyl]glycine, octyl ester (3.7 g, 6.16 mm), was dissolved in 30 ml of tetrahydrofuran containing 6 ml of water and cooled to 0° C. on an ice bath. The solution was stirred and sodium tetrahydrido boron (234 mg, 6.16 mm) was added portionwise over about 10 minutes. The solution was allowed to warm to room temperature and stirred for an additional 35 minutes. (a) The solvent was removed by evaporation under vacuum and the residue was washed with water. The water washings were saturated with sodium chloride and the aqueous layer and the insoluble residue were simultaneously extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated in vacuo. A thin layer chromatograph of the residue indicated that the starting material was still present. The remainder of this residue was dissolved in tetrahydrofuran (30 ml), H2O (6 ml) and sodium tetrahydridoboron (234 mg) was added with stirring. The solution was stirred for 2 hours. This solution was then treated as in step (a). The resulting residue from the repeat of step (a) was then chromatographed on silica gel employing ether to yield N-[bis(N-methyl-N-benzylamino)phosphinothioylmethyl]glycine, octyl ester (700 mg) having a refractive index ND25 =1.5404.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18].CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])/[C:9](/[N+:10]([O-:12])=[O:11])=[CH:16]\[N:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: O=C(C[N+](=O)[O-])c1ccc(Br)cc1
Reactant: COC(OC)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CN(C)/C=C(\C(=O)c1ccc(Br)cc1)[N+](=O)[O-]
Temperature: 25 °C
Yield: 42.5 %

Procedure:
A mixture of 1-(4-bromophenyl)-2-nitroethanone (5.38 g, 0.022 mol, Seter J. et al., Isr. J. Chem., 4, 7 (1966)) and N,N-dimethylformamide dimethylacetal (2.9 g, 0.024 mol) and catalytic amount of p-TsOH in THF (100 mL) was refluxed for 10 h. The mixture was cooled to room temperature and concentrated in vacuo. The reaction mixture was purified by flash chromatography eluting with ethyl acetate/hexane (1/1) to give title compound (2.8 g, 43%).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:6]=1)([F:4])[CH3:3].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>>[F:4][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1cc(N)n(-c2cccnc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Product: CC(F)(F)c1cc(NC(=O)Oc2ccccc2)n(-c2cccnc2)n1
Yield: 28.9 %

Procedure:
Following the procedure in Example 118A, 3-(1,1-difluoroethyl)-1-(pyridin-3-yl)-1H-pyrazol-5-amine (60 mg, 0.27 mmol) was treated with phenyl chloroformate (0.13 mL, 1.07 mmol) to afford phenyl 3-(1,1-difluoroethyl)-1-(pyridin-3-yl)-1H-pyrazol-5-ylcarbamate (27 mg, 0.078 mmol, 30%). 1H NMR (300 MHz, MeOD) δ 8.90 (s, 1H), 8.70 (s, 1H), 8.15 (d, 1H), 7.69 (d, 1H), 7.44-7.12 (m, 5H), 4.87 (s, 3H); LC-MS (ESI) m/z 345 (M+H)+.