Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]([Si:16]([CH3:26])([CH3:25])[O:17][CH2:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH:21]=O)([CH3:15])([CH3:14])[CH3:13].C[O-].[Na+]>CO>[C:12]([Si:16]([CH3:25])([CH3:26])[O:17][CH2:18][C:19]([CH3:24])([CH3:23])[CH2:20]/[CH:21]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC(C)(CC=O)CO[Si](C)(C)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C/C=C1\C(=O)Nc2cc(Cl)ccc21)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.6 %

Procedure:
To the mixture of 6-chlorooxindole (2.1 g, 12.6 mmol) (Crescent) and 4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butyraldehyde (2.9 g, 12.6 mmol) in methanol (80 mL) was added a methanolic solution (25%, Aldrich) of sodium methoxide (4.08 g, 18.9 mmol) dropwise. The reaction mixture was stirred at room temperature for 10 min. The solvent was removed, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography (20% EtOAc in hexanes) to give E/Z-3-[4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butylidene]-6-chloro-1,3-dihydro-indol-2-one as a yellow oil (Yield 4.1 g, 84%).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].[C:11]([O:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:13])[CH3:12].Cl>C(Cl)Cl>[C:11]([O:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[CH:19][CH:18]=1)(=[O:13])[CH3:12]
Reactant: CC(C)C(=O)Cl
Reactant: CC(=O)OCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)OCCc1ccc(C(=O)C(C)C)cc1
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
Isobutyryl chloride (114 g, 1.07 mol) is added drop wise at −5 to 0° C. over 40 minutes to 295 g (2.21 mol) of anhydrous aluminum chloride in 160 ml of methylene chloride. Stirring is continued for 30 min, and 2-phenylethyl acetate (164.2 g, 1.00 mol) is then added drop wise at −5 to 0° C. over 2 hours. The mixture is stirred an additional 4 hours at −5 to 0° C., and then poured into a mixture of concentrated hydrochloric acid and ice. The organic layer is washed with water, dried and concentrated to give 190.5 g of crude 2-(4-isobutyrylphenyl)ethyl acetate, a colorless liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=2)=[CH:6][N:5]=1)([O-])=O>CO.[C].[Pd]>[NH2:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[N:5][CH:6]=1
Reactant: O=[N+]([O-])c1cccc(Oc2ccc([N+](=O)[O-])nc2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(Oc2ccc(N)nc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.1 %

Procedure:
To a solution of 2-nitro-5-(3-nitrophenoxy)pyridine (1.33 g, 5.07 mmol) in methanol (10 mL) was added palladium carbon (50% water-containing product, 100 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 12 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure and dried to give the title compound (980 mg, 96%) as a yellow oil.
Reaction SMILES: [C:1]1([S:7][S:8]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][NH:11][C:12]([F:14])=[O:13]>>[CH3:10][N:11]([S:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:12]([F:14])=[O:13]
Reactant: ClSSc1ccccc1
Reactant: CNC(=O)F
Product: CN(SSc1ccccc1)C(=O)F

Procedure:
Prepared by the procedure of Example II by reacting phenylthiosulfenyl chloride with methylcarbamoyl fluoride. b.p. 100°-110° C/0.3 Torr ND22.5 1.5770.
Reaction SMILES: [CH:1]1([N:4]([CH2:11][C:12]2[CH:13]=[C:14]([CH:41]=[CH:42][CH:43]=2)[C:15]([NH:17][C:18]2[S:19][C:20]3[CH2:40][CH2:39][CH2:38][CH2:37][C:21]=3[C:22]=2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[CH:28][CH:27]=2)=[O:24])=[O:16])[CH:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Br[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>>[CH2:49]([O:48][C:46](=[O:47])[CH2:45][N:8]1[CH2:7][CH2:6][CH:5]([N:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:11][C:12]2[CH:43]=[CH:42][CH:41]=[C:14]([C:15](=[O:16])[NH:17][C:18]3[S:19][C:20]4[CH2:40][CH2:39][CH2:38][CH2:37][C:21]=4[C:22]=3[C:23](=[O:24])[NH:25][C:26]3[CH:27]=[CH:28][C:29]([N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[CH:30][CH:31]=3)[CH:13]=2)[CH2:10][CH2:9]1)[CH3:50]
Reactant: CCOC(=O)CBr
Reactant: CCN(CC)c1ccc(NC(=O)c2c(NC(=O)c3cccc(CN(C4CCNCC4)C4CC4)c3)sc3c2CCCC3)cc1
Product: CCOC(=O)CN1CCC(N(Cc2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(N(CC)CC)cc3)CCCC4)c2)C2CC2)CC1
Yield: 79.7 %

Procedure:
By using 340 mg of 2-[(3-{[cyclopropyl(piperidin-4-yl)amino]methyl}benzoyl)amino]-N-[4-(diethylamino)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide and 99 mg of ethyl bromoacetate, a reaction was performed under the conditions similar to Preparation Example 30, thereby obtaining 310 mg of ethyl[4-(cyclopropyl {3-[(3-{[4-(diethylamino)phenyl]carbamoyl}-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)carbamoyl]benzyl}amino)piperidin-1-yl]acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:20]=[CH:21][C:22]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])=[N:23][CH:24]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.Cl.O1CCOCC1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:20]=[CH:21][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[N:23][CH:24]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CC(=O)OC(C)(C)C)nc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CC(=O)O)nc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
tert-Butyl 2-(5-(3-methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyridin-2-yl)acetate (25 mg, 0.056 mmol) was added to HCl in dioxane (0.5 ml, 2.000 mmol, 4M). The mixture was stirred at room temperature for 1 hour. The solid was collected by the filtration and afforded 2-(5-(3-methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyridin-2-yl)acetic acid (14.1 mg, 0.033 mmol). MS ESI calc'd. for C19H16F3N4O2 [M+H]+ 389. found 389. 1H NMR (500 MHz, CD3OD): δ 9.07 (d, J=1.5 Hz, 1H), 8.83 (dd, J=8.0, 1.5 Hz, 1H), 8.73 (d, J=5.0 Hz, 1H), 8.15-8.10 (m, 2H), 7.66 (s, 1H), 7.34 (s, 1H), 7.18 (d, J=5.0 Hz, 1H), 4.25 (s, 2H), 2.46 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[S:13][C:14]([C:16]([N:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[CH3:19])=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9][O:8][C:7]=2[CH:27]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:18]([CH3:19])[C:16]([C:14]1[S:13][C:12]2[C:6]3[CH:5]=[CH:4][C:3]([CH2:2][N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[CH:27][C:7]=3[O:8][CH2:9][CH2:10][C:11]=2[CH:15]=1)=[O:17]
Reactant: CN1CCNCC1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(CBr)cc1OCC2)c1ccccc1Cl
Product: CN1CCN(Cc2ccc3c(c2)OCCc2cc(C(=O)N(C)c4ccccc4Cl)sc2-3)CC1

Procedure:
8-(Bromomethyl)-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide was reacted with N-methylpiperazine using the procedure of Example 153 for 243 to give 241. MS: (ESI+) 482.0
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=O)=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.ClC1N=[C:17]([O:19]C)C([N+]([O-])=O)=CC=1>>[Cl:11][C:4]1[N:3]=[C:2]([O:19][CH3:17])[C:7]([C:8]#[N:10])=[CH:6][CH:5]=1
Reactant: COc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Product: COc1nc(Cl)ccc1C#N

Procedure:
6-chloro-2-methoxypyridine-3-carbonitrile was prepared from 2,6-dichloropyridine-3-carboxamide in accordance with the procedure described above for the preparation of 6-chloro-2-methoxy-3-nitro-pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14](=[N:16][O:17][CH2:18][CH:19]=[CH2:20])[CH3:15])=[C:10]([S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14](=[N:16][O:17][CH2:18][CH:19]=[CH2:20])[CH3:15])=[C:10]([S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C=CCON=C(C)COc1c(S(=O)(=O)CC)ccc(C(=O)OC)c1Cl
Agent: [Na+]
Agent: [OH-]
Product: C=CCON=C(C)COc1c(S(=O)(=O)CC)ccc(C(=O)O)c1Cl

Procedure:
0.540 g (about 1.40 mmol) of methyl 2-chloro-3-(2-allyloxyiminopropyloxy)-4-ethanesulfonylbenzoate and 0.061 g (1.50 mmol) of NaOH were reacted analogously to preparation c).
Reaction SMILES: Br[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([N:10]2[CH2:22][CH2:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])[C:3]=1[CH:4]=[O:5].[CH3:24][C@H:25]1[CH2:30][N:29]([CH:31]2[CH2:34][O:33][CH2:32]2)[C@H:28]([CH3:35])[CH2:27][N:26]1[C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]2[C:44](=[O:59])[N:45]([CH3:58])[CH:46]=[C:47](B3OC(C)(C)C(C)(C)O3)[CH:48]=2)=[N:40][CH:41]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[CH3:24][C@H:25]1[CH2:30][N:29]([CH:31]2[CH2:34][O:33][CH2:32]2)[C@H:28]([CH3:35])[CH2:27][N:26]1[C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]2[C:44](=[O:59])[N:45]([CH3:58])[CH:46]=[C:47]([C:2]3[CH:9]=[N:8][CH:7]=[C:6]([N:10]4[CH2:22][CH2:21][N:13]5[C:14]6[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=6[CH:20]=[C:12]5[C:11]4=[O:23])[C:3]=3[CH2:4][OH:5])[CH:48]=2)=[N:40][CH:41]=1
Reactant: O=Cc1c(Br)cncc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4cncc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Temperature: 25 °C
Yield: 9.9 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 3-bromo-5-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2a]indol-2(1H)-yl)isonicotinaldehyde 101f (200 mg, 0.54 mmol), 3-(5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 155a (267 mg, 0.54 mmol), Pd(dppf)Cl2 (44 mg, 0.054 mmol), K3PO4 (229 mg, 1.08 mmol), sodium acetate (89 mg, 1.08 mmol), water (0.2 mL) and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 157 (35.5 mg, 11%) as a yellow solid. MS-ESI: [M+H]+ 665.4. 1H NMR (500 MHz, CDCl3) δ 8.65-8.63 (m, 2H), 8.50 (s, 1H), 7.80 (s, 1H), 7.87 (s, 1H), 7.48-7.47 (m, 1H), 7.36 (d, J=7.5 Hz, 1H), 6.88 (s, 1H), 6.81 (d, J=9.0 Hz, 1H), 4.75-4.54 (m, overlap, 6H), 4.37-4.13 (m, overlap, 4H), 4.00-3.95 (m, 1H), 3.74-3.73 (m, 1H), 3.72 (s, 3H), 3.19-3.15 (m, 1H), 2.91-2.90 (m, 1H), 2.74-2.44 (m, overlap, 7H), 1.92-1.88 (m, 2H), 1.81-1.79 (m, 2H), 0.90-0.89 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:48][CH2:49][CH2:50][O:51][C:52]([CH3:73])([CH3:72])[CH2:53][N:54]1[C:66]2[C:65]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[N:59]=[C:58]([NH2:67])[C:57]=2[N:56]=[C:55]1[CH2:68][O:69][CH2:70][CH3:71]>CN(C=O)C>[NH2:67][C:58]1[C:57]2[N:56]=[C:55]([CH2:68][O:69][CH2:70][CH3:71])[N:54]([CH2:53][C:52]([CH3:73])([O:51][CH2:50][CH2:49][NH:48][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:72])[C:66]=2[C:65]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[N:59]=1
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCNC(=O)CCCCCNC(=O)OC(C)(C)C
Yield: 27.8 %

Procedure:
6-(tert-Butoxycarbonylamino)hexanoic acid (197 mg, 850 μmol) was combined with DMF (10.9 mL) to give a colorless solution. O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU, 300 mg, 936 μmol) and N,N-diisopropylethylamine (DIEA, 728 μl, 4.25 mmol) were added with stirring in an inert atmosphere. Then 1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (Example 1c, 304 mg, 850 μmol) was added and the mixture was stirred for 2 hours at room temperature. The mixture was concentrated in vacuo, dissolved in ethyl acetate (5 mL), stirred for 1 min with cold sodium hydroxide solution (1 N) and dried by passing through ChemElut® (10 g). The organic phase was concentrated in vacuo again and the residue was purified by flash chromatography (silica gel, 10% methanol in dichloromethane) to give the title compound (0.135 g, 23%) as light brown oil; LC-MS (UV peak area, ESI) 83%, 571.5 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH:29]([CH3:33])[CH2:30][C:31]=4[N:32]=3)=[O:23])[CH:18]([C:34](=[O:45])[NH:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43]C)[CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.B(Br)(Br)Br.ClCCl.CO.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH:29]([CH3:33])[CH2:30][C:31]=4[N:32]=3)=[O:23])[CH:18]([C:34](=[O:45])[NH:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[OH:43])[CH2:17]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccccc1CNC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1nc2c(s1)CNC(C)C2
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3C(=O)NCc3ccccc3O)sc2CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In dichloromethane (10 ml), 4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-[[N-(2-methoxybenzyl)]carbamoyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride (195 mg) was dissolved, followed by the dropwise addition of a boron tribromide-dichloromethane solution (1.0M, 2.08 ml) at −78° C. The reaction mixture was heated to room temperature and stirred overnight. To the reaction mixture, methanol (2 ml), sodium carbonate (200 mg) and water (3 ml) were added to extract the organic layer, followed by drying over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The solid thus precipitated was collected by filtration while being washed with 1N hydrochloric acid, whereby the title compound (50 mg, 24%) was obtained as a pale yellow solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.N1C=CC=CC=1>C(#N)C>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([S:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Fc1ccc(S)cc1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(=O)Oc1ccc(C(=O)Sc2ccc(F)cc2)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A solution of 4-acetoxybenzoyl chloride (7.74 g) in dry acetonitrile (10 ml) was added to a solution of 4-fluorothiophenol (5.00 g) in acetonitrile (40 ml). The mixture was cooled to 5° C. by immersion in an ice-water bath and pyridine (3.15 ml) added dropwise to the stirred solution. The mixture was stirred at 5° C. for 1 hour, allowed to reach room temperature and stirred for a further 2 hours, and then the solvents were evaporated in vacuo. The residue was partitioned between ethyl acetate and water and the separated organic layer was washed successively with water, dilute hydrochloric acid, and water again. Evaporation of the solution, which had been dried over magnesium sulphate, afforded the desired thioester as a pale yellow solid (10.81 g).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([O:31][CH2:32][CH3:33])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][CH:16]=2)=[CH:9][C:8]=1[CH3:30])C.[Li+].[OH-]>>[CH2:32]([O:31][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=3)=[N:17][CH:16]=2)=[CH:9][C:8]=1[CH3:30])[C:4]([OH:34])=[O:3])[CH3:33]
Reactant: CCOC(=O)C(Cc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)s2)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)s2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-2-ethoxy-3-{2-methyl-4-[2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-{2-methyl-4-[2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionic acid as off-white solid.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>CN(C=O)C>[CH3:17][N:18]([CH3:20])[CH:19]=[C:8]([N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]1=[O:1])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)Cn1ccccc1=O
Reactant: CCOC(OCC)N(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN(C)C)n1ccccc1=O
Yield: 84.5 %

Procedure:
Combined ethyl 2-(2-oxopyridin-1(2H)-yl)acetate (500 mg, 2.76 mmol), 1,1-diethoxy-N,N-dimethylmethanamine (2031 mg, 13.80 mmol) and DMF (2 mL) and heated at 100° C. for 15 h. The reaction mixture was diluted with xylenes and concentrated onto Celite® then purified on a 30 g NH silica column (Moritex) eluted with 0 to 100% EtOAc in hexanes to give the title compound (551 mg, 85% yield) as a light yellow solid. MS m/z 237 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (br. s., 3 H) 2.77 (br. s., 6 H) 3.94-4.08 (m, 2 H) 6.17 (td, J=6.7, 1.3 Hz, 1 H) 6.36 (dt, J=9.0, 1.1 Hz, 1 H) 7.35-7.45 (m, 2 H) 7.47 (s, 1 H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:12][CH3:13])[CH:8]([NH2:9])[CH2:7][CH2:6][CH2:5][C:4]1([CH3:11])[NH2:10])[CH3:2]>[Pt].C(C(C)=O)C>[CH:1]([NH:10][C:4]1([CH3:11])[CH2:5][CH2:6][CH2:7][CH:8]([NH:9][CH:6]([CH2:7][CH3:8])[CH3:5])[C:3]1([CH2:1][CH3:2])[CH2:12][CH3:13])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC1(CC)C(N)CCCC1(C)N
Agent: [Pt]
Solvent: CCC(C)=O
Product: CCC(C)NC1CCCC(C)(NC(C)CC)C1(CC)CC
Temperature: 130 °C
Yield: 95 %

Procedure:
Diethyl(methyl)-1,3-cyclohexanediamine, as a mixture of its 2,4-diethyl-6-methyl- and 4,6-diethyl-2-methyl-isomers (3.0 g), Pt(S)/C (0.4 g), Amberlyst-15 (0.4 g), and methyl ethyl ketone (45 g) were charged into a 100 mL metal autoclave at 22° C. The closed autoclave was purged 3 times with 125 psig (9.63×105 Pa) of H2 at 22° C. to remove traces of air. The reaction mixture was then heated at 130° C. under 125 psig (9.63×105 Pa) of H2 for 6 hrs (until no further H2 uptake was observed). The product mixture was cooled to 22° C. and degassed. A diluted product sample was analyzed by GC (100° C. for 5 minutes at 10° C. per minute rate; final temperature, 270° C.). The GC data (normalization method) showed 100% conversion of diethyl(methyl)-1,3-cyclohexanediamine, and a 95-97% yield of N,N′-di-sec-butyl-[diethyl(methyl)-1,3-cyclohexanediamine].
Reaction SMILES: CN(C)C=O.[CH2:6]([O:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]2[N:26]=[C:25]([CH3:27])[O:24][N:23]=2)=[C:16](I)[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C]=O.Cl.[C:32]([O:35][CH2:36]C)(=[O:34])C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(N(CC)CC)C.CO>[CH2:6]([O:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]2[N:26]=[C:25]([CH3:27])[O:24][N:23]=2)=[C:16]([CH:15]=1)[C:32]([O:35][CH3:36])=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1cc(-c2noc(C)n2)c(I)cc1OCc1ccccc1
Reactant: CCOC(C)=O
Agent: [Fe+2]
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(OCc2ccccc2)c(OC)cc1-c1noc(C)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of tris(dibenzylideneacetone)dipalladium (0) (163 mg), 1,1′-bis(diphenylphosphino)ferrocene (394 mg) and N,N-dimethylformamide (10 mL) was stirred under an argon atmosphere for 10 minutes. 3-(4-Benzyloxy-2-iodo-5-methoxy-phenyl)-5-methyl-[1,2,4]oxadiazole (reference example 4-1) (1.5 g), methanol (15 mL) and triethylamine (1.5 mL) were added to the mixture. After displacement to a carbon monoxide atmosphere, the mixture was stirred at 90° C. for 16 hours. After cooling to room temperature, ethyl acetate and 2 mol/L hydrochloric acid were added to the mixture. The separated organic layer was washed with water, a 2 mol/L aqueous solution of sodium hydroxide, an aqueous solution of sodium bicarbonate and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 15%-30% ethyl acetate/hexane, gradient elution) to give the title compound (1.1 g).
Reaction SMILES: CO[C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:15]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:14]=2[CH:33]=1.[CH3:35][O:36][CH2:37][CH2:38][CH2:39][NH2:40]>>[CH3:35][O:36][CH2:37][CH2:38][CH2:39][NH:40][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:15]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:14]=2[CH:33]=1
Reactant: COC(=O)CCCCCOc1ccc2nc(SCc3ccccc3)n(-c3ccc(C)cc3)c2c1
Reactant: COCCCN
Product: COCCCNC(=O)CCCCCOc1ccc2nc(SCc3ccccc3)n(-c3ccc(C)cc3)c2c1

Procedure:
100 mg of 6-[[2-benzylmercapto-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was reacted with 3-methoxypropylamine according to general operating instructions 4. 53 mg was obtained.
Reaction SMILES: C(=O)=O.C(Cl)(Cl)(Cl)Cl.[Cl:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[O:12].N(CCO)CCO>C1COCC1>[Cl:9][CH2:10][C@@H:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[OH:12]
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: OCCNCCO
Product: O[C@@H](CCl)c1ccc(Cl)cc1Cl
Temperature: -25 °C
Reaction time: 7 h
Yield: 112 %

Procedure:
To a solution containing 16 g (49.90 mmol) of (−)-DIP-Cl in 30 mL of anhydrous THF, at −25° C. (dry ice, CCl4), under nitrogen, was added 10 g (44.74 mmol) of 2,2′,4′-trichloroacetophenone. The stoppered solution was stirred at −25° C. for about 7 hours, and then at room temperature overnight. THF was removed in vacuo, and (+)-α-pinene was removed under high vacuum at room temperature overnight. The resulting viscous colorless oil was dissolved in 200 mL of anhydrous ether, and cooled to 0° C. Diethanolamine (10.50 g, 0.10 mol) was added to the filtrate, and stirring was continued for 3 hours at room temperature. The white solid obtained was removed by filtration and washed with anhydrous ether. The colorless solution was evaporated to dryness to yield a viscous colorless oil. This oil was flash chromatographed on silica gel, first with hexanes to remove (+)-α-pinene. The product was eluted from the column with 93% hexanes/7% acetone to yield 11.30 g of a white solid. This solid was crystallized from hexanes at 0° C. Yield: 5.75 g (57%); TLC: 95% hexanes/5% acetone, Rf=0.10.