Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[C:9](=[O:12])([O-])[O-].[K+].[K+].I[CH3:16]>CC(C)=O>[CH3:16][C:2]1([CH3:1])[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:9]1=[O:12]
Reactant: O=C([O-])[O-]
Reactant: CI
Reactant: O=C1CCCC(=O)C1
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)C(=O)CCCC1=O
Yield: 28 %

Procedure:
A mixture of cyclohexane-1,3-dione (10.0 g, 89.3 mmol), potassium carbonate (24.6 g, 178.6 mmol) and iodomethane (28.5 g, 201 mmol) in acetone (50 mL) was refluxed overnight. After completion, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (5-10% ethyl acetate in petroleum ether) to afford the title compound (3.5 g, 25.0 mmol, 28% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 2.69 (t, J=6.8 Hz, 4H), 1.52 (m, 2H) 1.31 (s, 6H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=[O:17].[C:40](O)(=[O:43])[CH:41]=[CH2:42]>CN(C)C1C=CN=CC=1.ClCCl>[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40](=[O:43])[CH:41]=[CH2:42])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: C=CC(=O)O
Reactant: O=Cc1ccc(-c2ccc(OCCCCCCCCO)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCCCOc1ccc(-c2ccc(C=O)cc2)cc1
Reaction time: 8 h
Yield: 56.4 %

Procedure:
2.9 g of N,N'-dicyclohexylcarbodiimide were added within 5 minutes while stirring to a solution of 3.8 g of 4-formyl-4'-(8-hydroxyoctyloxy)biphenyl, 0.9 g of acrylic acid and 0.05 g of 4-(dimethylamino)pyridine in 25 ml of dichloromethane. The reaction mixture was stirred overnight, filtered and then concentrated. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 8:2) and recrystallization from ethyl alcohol of the fractions which were pure according to thin-layer chromatography gave 2.5 g of 4-formyl-4'-(8-acryloyloxyoctyloxy)biphenyl.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([NH:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[O:14])=[CH:11][C:10]=1[C:26]([CH3:29])([CH3:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])=[CH:11][C:10]=1[C:26]([CH3:29])([CH3:28])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(OCc2ccccc2)c(C(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)NCC(=O)O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 86.4 %

Procedure:
To a solution of tert-butyl 2-(4-(benzyloxy)-3-tert-butylbenzamido)acetate (3.37 g, 8.48 mmol) in CH2Cl2 (100 mL) at 0° C. was added TFA (10 mL) and the mixture was stirred at room temperature under nitrogen atmosphere for 10 h. The reaction mixture was concentrated in vacuo to dryness to give 2-(4-(benzyloxy)-3-tert-butylbenzamido)acetic acid (2.50 g, 86%) as a white powder: mp 172-174° C.; 1H NMR (300 MHz, CD3OD) δ 7.86 (s, 1H), 7.74-7.70 (m, 1H), 7.50-7.30 (m, 5H), 7.10-7.05 (m, 1H), 5.18 (s, 2H), 4.07 (s, 2H), 1.41 (s, 9H); IR (film) 3497, 3062, 3031, 2931, 2865, 1447, 1289, 1139, 1085, 1062 cm−1; MS found: (M+H)+=342.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:13](Br)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1)[CH3:14]
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc(CC(=O)OC)c1
Reaction time: 24 h

Procedure:
Methyl 3-hydroxyphenylacetate (6.4 g, 38.5 mmol) was dissolved in acetone (50 mL). Ethyl bromide (3.5 mL, 46.9 mmol) was added, followed by potassium carbonate (6.37 g, 46 mmol). The reaction was heated to reflux. After 24 hours, more ethyl bromide (3.55 mL, 46.9 mmol) was added and the reaction refluxed for a further 24 hours. The mixture was cooled, filtered and rotary evaporated. The product was dissolved in ethyl acetate and the solution washed with saturated sodium bicarbonate (2×50 mL) and brine, and dried (MgSO4). Removal of solvent revealed methyl 3-ethoxyphenylacetate as an oil that crystallized upon standing. 1H NMR (500 MHz, CDCl3) δ 7.25 (1H, dd), 6.87 (3H, m), 4.08 (2H, q), 3.73 (3H, s), 3.65 (2H, s), 1.45 (3H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6]O.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][Br:13]
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccccc1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccccc1CCBr
Temperature: 0 °C
Yield: 93.5 %

Procedure:
A mixture of 2-methoxyphenethyl alcohol (500 mg) and carbon tetrabromide (1.53 g) in anhydrous dichloromethane (10 mL) was stirred at 0° C. under a nitrogen atmosphere. After adding triphenylphosphine (1.03 g) portionwise, the reaction mixture was stirred for an hour under the same condition. The reaction mixture was evaporated in vacuo and the residue was subjected to a silica gel column chromatography eluting with n-hexane only and then a mixture of n-hexane and ethyl acetate (40:1 to 20:1) to give 2-methoxyphenethyl bromide (661 mg) as an oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([NH2:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[Br:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([S:25](Cl)(=[O:27])=[O:26])=[C:20]([Cl:29])[CH:19]=1>N1C=CC=CC=1.Cl.C(OCC)(=O)C>[Br:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([S:25]([NH:14][CH:3]([CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[C:2]([F:1])([F:15])[F:16])(=[O:26])=[O:27])=[C:20]([Cl:29])[CH:19]=1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Br)cc1Cl
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=S(=O)(NC(Cc1c[nH]c2ccccc12)C(F)(F)F)c1c(Cl)cc(Br)cc1Cl
Temperature: 65 °C
Reaction time: 16 h
Yield: 28.9 %

Procedure:
A mixture of 170 mg (0.75 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine and 243 mg (0.75 mmol) of 4-bromo-2,6-dichlorobenzensulfonyl chloride in 4 mL of pyridine was warmed at 65° C. The reaction was monitored by TLC indicating a new less polar product compared to amine. After 16 hours, the mixture was cooled and concentrated to afford a thick oily residue. The residue was diluted with 1 N aqueous hydrochloric acid until acidic and extracted with ethyl acetate. The combined organic layers were washed with 1 N aqueous HCl, saturated aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, decanted, and concentrated in vacuo. The crude material was purified by preparative TLC using EtOAc-hexanes (15:85). Material from the preparative TLC was isolated by suspending the silica gel in ethyl acetate followed by filtration. The filtrate was concentrated in vacuo to afford 112 mg (30%) of the title compounds as an off-white crystalline solid.
Reaction SMILES: [Na].[CH2:2]([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:3].[Na][C:16](C(CC)(CC)C)(C([O-])=O)[C:17]([O-])=O.O.[C:30]1([CH3:37])[C:31](C)=[CH:32][CH:33]=[CH:34][CH:35]=1>C1(C)C=CC=CC=1>[CH2:8]([O:7][C:5](=[O:6])[C:4]([CH2:16][CH3:17])([CH2:2][CH2:3][CH2:37][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9]
Reactant: CCC(C)(CC)C([Na])(C(=O)[O-])C(=O)[O-]
Reactant: CCOC(=O)C(CC)C(=O)OCC
Reactant: Cc1ccccc1C
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(CC)(CCCC1CCCCC1)C(=O)OCC
Temperature: 150 °C
Reaction time: 10 h

Procedure:
Sodium metal (3.16 g, 0.137 g/atom) was dispersed by heating with rapid stirring in 80 ml of dry xylene at 110° to 120° C. The mixture was cooled and the xylene was removed with a filter stick. Dry toluene (300 ml distilled from calcium hydride) was added thereto and followed by the addition of 28.17 g (0.149 mole) of diethyl ethylmalonate. This mixture was slowly heated to 150° C. 3-Cyclohexylpropyl-1-tosylate (28.3 g, 1.1956 mole; prepared by Example 10A) was dissolved in 80 ml of dry toluene. This solution was then added to the sodiodiethylethylmalonate above and the mixture was stirred at 150° C. for 10 hr. The mixture was cooled and poured into 500 ml of water. The phases were separated and the aqueous phase was extracted with 500 ml (2×250 ml) of ether. The ether extract was washed with 250 ml of saturated sodium chloride solution, dried over a anhydrous magnesium sulfate and filtered. The solvents were removed in vacuo. The product was distilled at reduced pressure to yield 19.4 g of the title compound having the following physical characteristics:
Reaction SMILES: [C:1](C(N)(CCC)C(O)=O)(=O)C1C=CC=CC=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.[C:31]([NH:39][CH:40]([C:44]([OH:46])=O)[CH:41]([CH3:43])C)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl.ClC1C=CC(C2CCNCC2)=CC=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([OH:30])[CH2:25][CH2:26][N:27]([C:44](=[O:46])[CH:40]([NH:39][C:31](=[O:38])[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:41][CH2:43][CH3:1])[CH2:28][CH2:29]2)=[CH:20][CH:19]=1
Reactant: CCCC(N)(C(=O)O)C(=O)c1ccccc1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: CC(C)C(NC(=O)c1ccccc1)C(=O)O
Agent: Cl
Agent: Clc1ccc(C2CCNCC2)cc1
Product: CCCC(NC(=O)c1ccccc1)C(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
Example 216 was prepared in a similar manner as described for the preparation of Example 208 with the exceptions that benzoyl-2-aminopentanoic acid and 4-(4-chlorophenyl)-4-hydroxypiperidine were substituted for benzoyl-DL-valine and 4-(4-chlorophenyl)piperidine hydrochloride, respectively. MS found: (M+H)+=415.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]2(=[O:23])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][N:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.C(Cl)Cl.[Br:27]Br>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([P:8]2(=[O:23])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][N:9]2[C:17]2[CH:18]=[CH:19][C:20]([Br:27])=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: O=P1(c2ccc(F)cc2)c2ccccc2CN1c1ccccc1
Reactant: BrBr
Solvent: ClCCl
Solvent: CCOCC
Product: O=P1(c2ccc(F)cc2)c2ccccc2CN1c1ccc(Br)cc1
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.0 g, 0.003 mol) in 25 ml. of methylene chloride was added dropwise a solution of bromine (0.8 g, 0.1 mol) in 25 ml. of methylene chloride with constant stirring. The reaction mixture was stirred for one hour and washed with water, then sodium bisulfite, again with water, dried over magnesium sulfate and concentrated in vacuo to yield a yellow solid. The yellow solid was slurried in anhydrous diethyl ether to yield 1-(4-fluorophenyl)-2-(4-bromophenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.7 g, 56.4% yield) as a white solid having a melting point of 201°-205° C. and the following analysis:
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[CH2:15][C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([CH2:15][C:16]3[NH:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]=3)[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccnc1N1CCNCC1
Reactant: ClCc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cccnc1N1CCN(Cc2nc3ccccc3[nH]2)CC1
Reaction time: 1.25 h
Yield: 36.2 %

Procedure:
The product of Example 28B (0.50 g, 2.76 mmol), 2-chloromethyl-1H-benzimidazole (0.48 g, 2.90 mmol), and cesium carbonate (1.8 g, 5.52 mmol) were combined in N,N-dimethylformamide (28 mL) at 23° C. and stirred for 1.25 hours. The mixture was concentrated under reduced pressure and rinsed with 10% methanol/dichloromethane. The solid was filtered off and the filtrate concentrated under reduced pressure. The residue was impregnated onto flash silica gel and chromatographed on flash silica gel (10% methanol/dichloromethane) to afford 311 mg (36% yield) of the title compound. mp 210-212°° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.62 (m, 4H), 3.43 (m, 4H), 3.78 (s, 2H), 6.87 (m, 1H), 7.14 (m, 2H), 7.50 (m, 3H), 8.00 (m, 1H); MS (APCI) m/e 312 (M+H)+; Anal. calcd for C17H18FN5 0.4 H2O: C, 64.10; H, 5.95; N, 21.98. Found: C, 64.16; H, 5.86; N, 21.95.
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1.Cl[CH:13]([S:23][CH3:24])[C:14]([NH:16][C:17]([CH3:22])([C:19]#[C:20][CH3:21])[CH3:18])=[O:15]>>[O:10]=[C:8]1[S:7][C:6]2[C:11]([CH2:21][C:20]#[C:19][C:17]([NH:16][C:14](=[O:15])[CH2:13][S:23][CH3:24])([CH3:18])[CH3:22])=[CH:2][CH:3]=[CH:4][C:5]=2[O:9]1
Reactant: O=c1oc2ccc(O)cc2s1
Reactant: CC#CC(C)(C)NC(=O)C(Cl)SC
Product: CSCC(=O)NC(C)(C)C#CCc1cccc2oc(=O)sc12

Procedure:
In a similar procedure, 5-hydroxy-1,3-benzoxathiol-2-one was reacted with 2-chloro-2-methylthio-N-(2-methylpent-3-yn-2-yl)acetamide to give 5-(2-oxo-1,3-benzoxathiolyl)-2-methylthio-N-(2-methylpent-3-yn-2-yl)acetamide (Compound No. 4 of Table 7).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:45])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:42]=[CH:41][C:34]([C:35]([O:37][CH2:38][CH2:39][OH:40])=[O:36])=[CH:33][C:32]=2[O:43][CH3:44])=[O:29])[CH:5]=[CH:6][CH:7]=1.[C:46]([O:50][C:51]([NH:53][CH:54]([CH3:58])[C:55](O)=[O:56])=[O:52])([CH3:49])([CH3:48])[CH3:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.CN(C1C=CC=CN=1)C>CN(C)C=O>[C:46]([O:50][C:51]([NH:53][C@H:54]([CH3:58])[C:55]([O:40][CH2:39][CH2:38][O:37][C:35](=[O:36])[C:34]1[CH:41]=[CH:42][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:45])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:29])=[C:32]([O:43][CH3:44])[CH:33]=1)=[O:56])=[O:52])([CH3:49])([CH3:48])[CH3:47]
Reactant: COc1cc(C(=O)OCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)OCCOC(=O)[C@@H](C)NC(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 90 %

Procedure:
In a manner similar to the method described in Example 3, chiral 2-hydroxyethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (Example 1, 105.2 mg, 0.159 mmol) was reacted with (R)-(2-(tert-butoxycarbonylamino)propanoic acid (Chem-Impex, 75 mg, 0.398 mmol), HATU (Bachem, 151 mg, 0398 mmol), N,N-diisopropylethylamine (104 mg, 0.14 mL, 0.802 mmol) and dimethylaminopyridine (Aldrich, 10.8 mg, 0.088 mmol) in dimethyl formamide (8 mL) to give chiral 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-((R)-2-tert-butoxycarbonylamino-propionyloxy)-ethyl ester as a white solid (119 mg, 89% yield). MS (ES+) m/z calcd. for C41H47Cl2F2N4O8 [(M+H)+]: 831. found: 831.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:26][C:25](=O)[O:24][C:22](=[O:23])[CH2:21]2)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH2:26][C:25]2[NH:10][C:5]3[CH:4]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:8]=[CH:7][C:6]=3[N:9]=2)[CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:19]=1.[ClH:13]
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Product: Cl
Product: O=C(O)CC(Cc1nc2ccc(C(F)(F)F)cc2[nH]1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.4, starting from commercial 4-trifluoromethyl-1,2-phenylenediamine and 3-(4-chlorophenyl)glutaric anhydride, 3-(4-chlorophenyl)-4-(5-trifluoromethyl-2-benzimidazolyl)butanoic acid•HCl was obtained as colourless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:14](=[S:15])[CH:13]2[CH:9]1[CH2:10][CH2:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:16]>CO>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][CH2:12][CH:13]1[C:14](=[S:15])[NH2:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(=S)C2CCCC21
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCCC1C(N)=S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 42 ml of 29% aqueous ammonia and 60 ml of methanol, 1.48 g of 6-tert-butoxycarbonyl-6-azabicyclo[3.2.0]heptane-7-thione was dissolved, followed by stirring at room temperature for 30 minutes. The solvent was azeotropically evaporated using benzene-ethanol, whereby 1.39 g of 2-(tert-butoxycarbonylamino)cyclopentanecarbothioamide was obtained as the crystal form.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]1=[O:18].C(N(CC)CC)C>ClCCl>[S:2]([O:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]1=[O:18])([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1sc2ccccc2n1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCn1c(=O)sc2ccccc21

Procedure:
Methanesulfonyl chloride (1.625 ml, 2.4 g, 21 mmol) in dichloromethane (10 ml) was added dropwise with stirring to 3-(2-hydroxyethyl)benzothiazolin-2-one (3.9 g, 20 mmol) (J. J. D'Amico and F. G. Bollinger; J. Heterocyclic Chemistry 1988, 25, 1601).and triethylamine (3.478 ml, 2.525 g, 25 mmol) in dichloromethane (80 ml) and stirred for one hour at room temperature. The reaction mixture was then washed with water and dried (MgSO4), filtered and the solvent evaporated in-vacuo to give the title product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([CH2:30][O:31][C:32]1[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=[CH:36][CH:37]=1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28](=[O:29])[CH2:30][O:31][C:32]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:4][CH:3]=2)[CH:35]=[CH:34][CH:33]=1)[CH3:26]
Reactant: CCOC(=O)COc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O/N=C(\CC(c1ccccc1)c1ccc(Br)cc1)c1ccncc1
Product: CCOC(=O)COc1cccc(-c2ccc(C(C/C(=N\O)c3ccncc3)c3ccccc3)cc2)c1

Procedure:
In analogy to example 22, from (E)-3-(4-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (example 5) and 3-(ethoxycarbonyl)methoxyphenylboronic acid pinacol ester was prepared the title compound as a colorless oil, MS (ESI+): m/z=481.3 ([M+H]+).
Reaction SMILES: FC(F)(F)C(O)=O.COC1C=CC([CH2:14][N:15](C)[C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[C:21]([C:28]4[CH:33]=[C:32]([NH2:34])[CH:31]=[CH:30][C:29]=4[Cl:35])[C:22](=[O:27])[N:23]3[CH3:26])=[CH:18][N:17]=2)=CC=1>C(Cl)Cl>[NH2:34][C:32]1[CH:31]=[CH:30][C:29]([Cl:35])=[C:28]([C:21]2[C:22](=[O:27])[N:23]([CH3:26])[C:24]3[C:19]([CH:20]=2)=[CH:18][N:17]=[C:16]([NH:15][CH3:14])[CH:25]=3)[CH:33]=1
Reactant: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)ccc2Cl)c(=O)n3C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc2c(cn1)cc(-c1cc(N)ccc1Cl)c(=O)n2C
Yield: 58.7 %

Procedure:
Trifluoroacetic acid (10 mL, 134 mmol) was added to a solution of 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chlorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (4 g, 9.2 mmol) in CH2Cl2 (50 mL). The mixture was heated to reflux for 3 hrs. The reaction mixture was concentrated under reduced pressure, dissolved in aq HCl solution and washed with EtOAc (3×50 mL). The aqueous layer was neutralized with saturated Na2CO3 solution to pH 8, and was extracted with EtOAc (3×50 mL). The combined extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography to give 3-(5-amino-2-chlorophenyl)-1-methyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (1.7 g, 58% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1 H), 7.63 (s, 1 H), 7.06-7.00 (m, 2 H), 6.54-6.50 (m, 2 H), 6.14 (s, 1 H), 5.21 (s, 2 H), 3.48 (s, 3 H), 2.84 (d, J=4.8 Hz, 3 H); MS (ESI) m/z: 314.9 [M+H]+.
Reaction SMILES: Br[C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:13]([O-:16])(=[S:15])[CH3:14].[K+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(OCC)(=O)C>[C:13]([S:15][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])(=[O:16])[CH3:14]
Reactant: O=C(O)[C@H](Br)Cc1ccccc1
Reactant: CC([O-])=S
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(=O)S[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 6 h

Procedure:
In a 3 l-jacketed reactor, with mechanical stirring, refrigerator and thermometer, (R)-2-bromo-3-phenyl-propionic acid (385.8 g, 1.68 moles), ethyl acetate (1,143 ml) and ALIQUAT 336° (4.2 g, 0.01 mole) were charged at 15° C. under nitrogen flow. The mixture temperature was brought to 0° C. and potassium thioacetate (222 g, 1.944 moles) was added in two portions. The reaction temperature was kept at 15° C. for 6 hours, then the mixture was twice washed with an aqueous solution of sodium thiosulfate pentahydrate (84.6 g in 820 ml of water over-all), then twice with demineralized water (600 ml total). The phases were separated and the organic one was concentrated under vacuum in a thermostated bath at 35-40° C. The resulting organic solution was cooled and filtered over celite, then added with ethyl acetate (600 ml). On the basis of the HPLC analysis, the yield in solution was equal to 87%.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:14])[C:6]2[S:11][C:10](=S)[N:9](C)[C:7]=2[N:8]=1)[CH3:2].Cl>[OH-].[Na+]>[CH2:1]([C:3]1[NH:4][C:5](=[O:14])[C:6]([SH:11])=[C:7]([NH:9][CH3:10])[N:8]=1)[CH3:2]
Reactant: CCc1nc2c(sc(=S)n2C)c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1nc(NC)c(S)c(=O)[nH]1
Temperature: 4 °C
Yield: 85.2 %

Procedure:
5-Ethyl-3-methyl-6H-thiazolo[4,5-d]pyrimidin-7-one-2-thione (9.5g, 41.8 mmole) from Example 108 was suspended in approximately 500ml of 4N sodium hydroxide solution. The resultant mixture was refluxed for 2 to 4 hours, followed by cooling at approximately 4° C. for about hours. The mixture was slowly acidified with concentrated hydrochloric acid; the solid was separated by filtration and dried, providing 6.6g (85%) of 2-ethyl-5-mercapto-6-methylamino-3H-pyrimidin-4-one. Infrared and nuclear magnetic resonance spectral analyses confirmed the structural assignment.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)(=[O:9])[C:7]#[CH:8]>C1COCC1>[CH2:1]([N:3]([CH2:4][CH3:5])[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:9])[CH3:2]
Reactant: C#CC(=O)Oc1ccc(-c2ccccc2)cc1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(C=CC(=O)Oc1ccc(-c2ccccc2)cc1)CC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
Diethylamine (66 mg, 0.89 mmol) and compound 1 (200 mg, 0.89 mmol) were dissolved in dry THF (20 mL), and the solution was stirred at RT for 15 min. The solvent was removed under reduced pressure to give the crude product which was then purified by column chromatography using ethyl acetate:hexane (7:3) to give compound 2 (237 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 1.24 (t, J=7.0 Hz, 6H), 3.28 (br. s, 4H), 4.79 (d, J=13.0 Hz, 1H), 7.20 (d, J=8.6 Hz, 2H), 7.36 (t, J=7.4 Hz, 1H), 7.44 (t, J=7.8 Hz, 2H), 7.62 (m, 4H), 7.63 (d, J=13.0 Hz, 1H). HRMS ESI (m/z): Calculated for C19H21NO2 ([M+H]+): 296.1572. found: 296.1647.