Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1[CH:7]=[C:8]([N:13]2[C:21](=[O:22])[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]2=[O:23])[CH:9]=[CH:10][C:11]=1[Cl:12])([OH:3])=[O:2].[CH:24]1(O)[CH2:28][CH2:27][CH2:26][CH2:25]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH:24]1([O:2][C:1]([CH2:4][S:5][C:6]2[CH:7]=[C:8]([N:13]3[C:21](=[O:22])[C:20]4[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=4[C:14]3=[O:23])[CH:9]=[CH:10][C:11]=2[Cl:12])=[O:3])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)CSc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Reactant: OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(CSc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl)OC1CCCC1
Yield: 44.3 %

Procedure:
2-(3-Carboxymethylthio-4-chlorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (3.61 g), cyclopentanol (1.24 g) and p-toluenesulfonic acid monohydrate (0.18 g) were suspended in toluene (10 ml), molecular sieve 3A (0.2 g) was added thereto, and the resultant mixture was heated under reflux for 6 hours. The reaction mixture was allowed to cool, admixed with water and extracted with toluene. The extract was washed with water, dried, and concentrated. The precipitated crystals were washed with methanol to give 1.91 g of 2-(3-cyclopentyloxycarbonylmethylthio-4-chlorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione. m.p., 57°-59° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24]S(C)(=O)=O)=[CH:16][CH:15]=2)[C@@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH:35]=[CH:36][CH:37]=[N:38]3)=[CH:33][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:41][C:42]([F:46])([F:45])[CH2:43]O.[H-].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:43][C:42]([F:46])([F:45])[F:41])=[CH:16][CH:15]=2)[C@@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH:35]=[CH:36][CH:37]=[N:38]3)=[CH:33][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOS(C)(=O)=O)cc2)[C@@H](OCc2ccc3cccnc3c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC(F)(F)F)cc2)[C@@H](OCc2ccc3cccnc3c2)C1

Procedure:
In analogy to the procedure described in example 23(e), the (3R,4R)-4-[4-(3-methanesulfonyloxy-propoxy)-phenyl]-3-(quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester [example 23(d)] was reacted with 2,2,2-trifluoro-ethanol and sodium hydride suspension in tetrahydrofuran to yield the (3R,4R)-3-(quinolin-7-ylmethoxy)-4-[4-[3-(2,2,2-trifluoro-ethoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as light yellow oil; MS: 575 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2=[N:15][C:16](S(C)(=O)=O)=[N:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:13]2[CH2:12][NH:11][C:10]1=[O:31].[NH2:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35]>CN1C(=O)CCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2=[N:15][C:16]([NH:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35])=[N:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:13]2[CH2:12][NH:11][C:10]1=[O:31]
Reactant: NC(CO)CO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1-c1nc(NC(CO)CO)nc2c1CNC(=O)N2c1c(F)cccc1F

Procedure:
The product of example 3 (90 mg, 0.2 mmol) was dissolved in NMP (1 mL) and serinol (91 mg, 1.0 mmol) was added. The solution was heated to 65° for 48 h, diluted with EtOAc (75 mL) and washed with 10% aq citric acid (2×), H2O, and satd aq NaCl, dried (Na2SO4), concentrated and purified by prep hplc to afford 46 mg (50%). LC MS m/z=460 (MH+), Rt=1.37 min
Reaction SMILES: [CH:1]1([N:4]([CH3:23])[C:5]2[C:6]3[C:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C:17]=4[S:16][C:7]=3[N:8]=[C:9]([CH2:11][O:12]C(=O)C)[N:10]=2)[CH2:3][CH2:2]1.O.[OH-].[Li+]>C1COCC1.O>[CH:1]1([N:4]([CH3:23])[C:5]2[C:6]3[C:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C:17]=4[S:16][C:7]=3[N:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)OCc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCC3
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1nc(CO)nc2sc3c(c12)CCCC3)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a solution of acetic acid 4-(cyclopropyl-methyl-amino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethyl ester (4 g, 0.012 mol) in THF (10 ml) and water (5 ml) was added lithium hydroxide monohydrate (1.48 g, 0.036 mol). The solution stirred at room temperature for 4 h. The volatiles were removed by distillation, and the residue was diluted with water, and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over anhydrous sodium sulphate, concentrated, and purified by chromatography on 60-120 silica gel using 25%-ethyl acetate in hexane to give the desired product [4-(cyclopropyl-methyl-amino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]-methanol (2.5 g, 72%) as off-white solid. 1H NMR (400 MHz, CDCl3): δ 0.45-0.50 (m, 2H), 0.72-0.80 (m, 2H), 1.72-1.80 (m, 2H), 1.88-1.94 (m, 2H), 2.82-2.94 (m, 5H), 3.07 (s, 3H), 3.94 (t, 1H), 4.70 (d, 2H); LC-MS: [M+H]=290.0 m/z.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([CH:13]1[CH:39]=[C:38]([CH3:40])[CH2:37][CH:36]([CH3:41])[CH2:35][CH:34]([O:42][CH3:43])[CH:33]2[O:44][C:29]([OH:48])([CH:30]([CH3:47])[CH2:31][CH:32]2[O:45][CH3:46])[C:28](=[O:49])[C:27](=[O:50])[N:26]2[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[C:20](=[O:51])[O:19][CH:18]([C:52]([CH3:63])=[CH:53][CH:54]2[CH2:59][CH2:58][CH:57]([OH:60])[CH:56]([O:61][CH3:62])[CH2:55]2)[CH:17]([CH3:64])[CH:16]([O:65][Si:66]([CH:73]([CH3:75])[CH3:74])([CH:70]([CH3:72])[CH3:71])[CH:67]([CH3:69])[CH3:68])[CH2:15][C:14]1=[O:76])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:11]([CH:13]1[CH:39]=[C:38]([CH3:40])[CH2:37][CH:36]([CH3:41])[CH2:35][CH:34]([O:42][CH3:43])[CH:33]2[O:44][C:29]([OH:48])([CH:30]([CH3:47])[CH2:31][CH:32]2[O:45][CH3:46])[C:28](=[O:49])[C:27](=[O:50])[N:26]2[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[C:20](=[O:51])[O:19][CH:18]([C:52]([CH3:63])=[CH:53][CH:54]2[CH2:59][CH2:58][C:57](=[O:60])[CH:56]([O:61][CH3:62])[CH2:55]2)[CH:17]([CH3:64])[CH:16]([O:65][Si:66]([CH:70]([CH3:72])[CH3:71])([CH:73]([CH3:75])[CH3:74])[CH:67]([CH3:69])[CH3:68])[CH2:15][C:14]1=[O:76])[CH3:12]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(OC)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a cooled solution (-78° C.) of oxalyl chloride (1.5 ml of 2M solution in CH2Cl2) was added dimethyl sulfoxide (361 mg) dropwise, followed by a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-14-triisopropylsiloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (947 mg) in dry methylene chloride (3 ml). The reaction mixture was stirred for 30 min. at -78° C. and then triethylamine (1 ml) was added. The reaction temperature was raised to room temperature, reaction was poured into water (20 ml), and extracted with ethyl acetate (three times). The combined organic layers were washed (water, sat'd NaHCO3), dried (anhydrous Na2SO4), and filtered. Removal of solvent followed by purification (silica gel chromatography, 40% ethyl acetate: 60% hexane) gave 870 mg of title compound.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[C:9]([NH2:15])=[N:10][CH:11]=[C:12]([Br:14])[N:13]=1.CN(C=O)C>CCOC(C)=O.O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:14][C:12]1[N:13]=[C:8]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[C:9]([NH2:15])=[N:10][CH:11]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
(Trimethylsilyl)acetylene (1.845 g, 2.655 mL, 18.78 mmol) was added dropwise to a solution of 3,5-dibromopyrazin-2-amine 1 (5 g, 19.77 mmol) in DMF (25 mL) Triethylamine (10.00 g, 13.77 mL, 98.85 mmol), copper(I) iodide (451.7 mg, 2.372 mmol) and Pd(PPh3)4 (1.142 g, 0.9885 mmol) were then added and the resulting solution stirred at RT for 30 minutes. The reaction mixture was diluted with EtOAc and water and the layers separated. The aqueous layer was extracted further with EtOAc and the combined organic layers washed with water, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography eluting with 15% EtOAc/Petroleum ether to give the product as a yellow solid (3.99 g, 75% Yield). 1H NMR (400.0 MHz, DMSO) d 0.30 (9H, s), 8.06 (1H, s); MS (ES+) 271.82
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14]C)=[O:13])=[CH:5][CH:4]=1)#[N:2].O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([OH:14])=[O:13])=[CH:19][CH:20]=1)#[N:2]
Reactant: COC(=O)c1cccc(COc2ccc(C#N)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(OCc2cccc(C(=O)O)c2)cc1

Procedure:
0.46 g of methyl 3-[(4-cyanophenoxy)methyl]benzoate and 175 mg of lithium hydroxide monohydrate were stirred in 7 ml of a solvent mixture of tetrahydrofuran, methanol and water (2:1:2) for 1 hour to hydrolyze the ester. The reaction mixture was added to 1 M of hydrochloric acid. The precipitate thus formed was taken by the filtration and then dried to obtain the title compound in the form of white crystals.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[C:5](=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][Si](C(C)(C)C)(C)C)[CH:16]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C(O)C>[OH:23][C:17]1[CH:16]=[C:15]([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:31])=[O:2])[C:5]=2[C:6]([OH:8])=[O:7])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COC(=O)c1cccc(Nc2ccc(OC)c(O[Si](C)(C)C(C)(C)C)c2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Nc2cccc(C(=O)O)c2C(=O)O)cc1O
Yield: 97.4 %

Procedure:
A mixture of 3-[3-(tert-butyldimethylsilanyloxy)-4-methoxyphenyl-amino]phthalic acid dimethyl ester (1.0 g, 2.2 mmol) and 3N NaOH (50 mL) in ethanol (100 mL) was heated to reflux for 2 hours. The mixture was cooled, and the solvent was removed under vacuum. The residue was dissolved in water (100 mL), washed with ethyl acetate (3×75 mL), acidified (HCl) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with water (3×75 mL), dried (MgSO4), and evaporated, providing 0.65 g of the product, in 96% yield: 1H NMR (DMSO-d6) δ 3.73 (s, 3H), 6.54 (dd, J=8.5 Hz, J=2.5 Hz, 1H), 6.60 (d, J=2.5 Hz, 1H), 6.86 (d, J=8.5 Hz, 1H), 6.98 (d, J=7.3 Hz, 1H), 7.13 (d, J=7.7 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.93 (s, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10](S(C2C=CC=CC=2)(=O)=O)[C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][C:15]([C:21]([O:23]C)=[O:22])=[CH:14]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.Cl>CO.CN(C)C=O>[C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cnc2ccc(N(S(=O)(=O)c3ccccc3)S(=O)(=O)c3ccccc3)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(O)c1cnc2ccc(NS(=O)(=O)c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 6-[bis(phenylsulfonyl)amino]quinoline-3-carboxylate (0.29 g, 0.601 mmol) in methanol (2.4 mL) was added a 1 M solution of sodium hydroxide in H2O (2.4 mL, 2.4 mmol). N,N-dimethylformamide (1 mL) was added to aid solubility and the resulting suspension was stirred at room temperature for 48 h. The reaction was then warmed to 60° C. and stirred for 96 h. A solution of hydrochloric acid (1.0 M in water) was added until pH=7. The mixture was extracted with ethyl acetate three times. The extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure and used as obtained (Int-12, 0.201 g, 61%). LC-MS: (FA) ES+ 329.
Reaction SMILES: Cl.[CH3:2][O:3][C@H:4]1[C@@H:9]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7][NH:6][CH2:5]1.Cl[C:22]1[CH:27]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[C:24]([CH3:32])[N:23]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:13]([O:12][C:11]([NH:10][C@H:9]1[CH2:8][CH2:7][N:6]([C:22]2[CH:27]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[C:24]([CH3:32])[N:23]=2)[CH2:5][C@H:4]1[O:3][CH3:2])=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Reactant: COC(=O)c1cc(C)nc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Product: COC(=O)c1cc(C)nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)c1
Yield: 7.4 %

Procedure:
The same operation as in Example (42a) was performed using benzyl cis(±)-[3-methoxypiperidin-4-yl]carbamate hydrochloride obtained in Example (160a) (384 mg, 1.45 mmol), methyl 2-chloro-6-methylpyridine-4-carboxylate (243 mg, 1.31 mmol), palladium acetate (32.7 mg, 0.15 mmol), BINAP (181 mg, 0.29 mmol) and cesium carbonate (1.42 g, 4.36 mmol), to obtain 40.1 mg of the title compound as a yellow oily substance (6.7%).
Reaction SMILES: C(C([NH:10][C:11]1[CH:30]=[CH:29][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][C:19](=[O:22])[C:18](=[C:23]3[S:27][CH:26]=[CH:25][S:24]3)[C:17]2=[O:28])=[CH:13][CH:12]=1)=O)C1C=CC=CC=1.[BrH:31].C(O)(=O)C.CCOCC>C(O)(=O)C>[BrH:31].[NH2:10][C:11]1[CH:30]=[CH:29][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][C:19](=[O:22])[C:18](=[C:23]3[S:24][CH:25]=[CH:26][S:27]3)[C:17]2=[O:28])=[CH:13][CH:12]=1
Reactant: O=C(Cc1ccccc1)Nc1ccc(CN2CCC(=O)C(=C3SC=CS3)C2=O)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: Nc1ccc(CN2CCC(=O)C(=C3SC=CS3)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 79.3 %

Procedure:
1-(p-(N-Benzylcarbonylamino)benzyl)-3-(1,3-dithiol-2-ylidene)-2,4-dioxopiperidine (100 mg) is dissolved in acetic acid (2 ml), and a 25% HBr-acetic acid solution (0.5 ml) is added thereto. The mixture is stirred at room temperature for 40 minutes, and then at 40°-50° C. for one hour. After cooling the mixture, ether is added to the mixture. The precipitated crystals are collected by filtration, and recrystallized from a mixture of methanol and ether to give 1-(p-aminobenzyl)-3-(1,3-dithiol-2-ylidene)-2,4-dioxopiperidine hydrobromide (70 mg, 79.3%) as pale yellow needles, m.p. 210°-214° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][O:8][C:9](=[O:31])[C@H:10]2[CH2:14][C@H:13]([O:15]C=O)[CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9](=[O:31])[C@H:10]2[CH2:14][C@H:13]([OH:15])[CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])=[CH:32][CH:33]=1
Reactant: COc1ccc(COC(=O)[C@H]2C[C@H](OC=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)[C@H]2C[C@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.17 h

Procedure:
215 mg of trans-1-p-nitrobenzyloxycarbonyl-4-formyloxy-D-proline p-methoxybenzyl ester was dissolved in 1.1 ml of tetrahydrofuran, and 0.93 ml of a 1N aqueous solution of sodium hydroxide was added to the resulting solution. After stirring for 10 minutes, the reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and distilled off to remove the solvent. The resulting residue was purified by silica gel thin layer chromatography to obtain trans-1-p-nitrobenzyloxycarbonyl-4-hydroxy-D-proline p-methoxybenzyl ester.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=[O:13])[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[CH:20]1([C:23]2[NH:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)[CH2:22][CH2:21]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CN(C=O)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]>[CH:20]1([C:23]2[N:24]([C:2]3[N:10]=[C:9]4[C:5]([N:6]=[C:7]([CH:12]=[O:13])[N:8]4[CH3:11])=[C:4]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[N:3]=3)[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)[CH2:22][CH2:21]1
Reactant: c1ccc2[nH]c(C3CC3)nc2c1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cn1c(C=O)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Temperature: 145 °C
Yield: 88.5 %

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (210 mg, 0.79 mmol), 2-cyclopropylbenzimidazole (150 mg, 0.95 mmol), tris(dibenzylideneacetone)dipalladium (44 mg, 0.05 mmol), Xphos (90 mg, 0.18 mmol) and Cs2CO3 (618 mg, 1.90 mmol) in dioxane (3 mL) and DMF (1 mL) was purged with argon then heated at 145° C. for 45 min in a microwave reactor. The reaction mixture was filtered through a pad of celite, washing with EtOAc. The filtrate was concentrated in vacuo and purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 0-75%) affording 2-(2-Cyclopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde as an orange solid (282 mg, 89%). LCMS (Method H): RT 3.79 min, [M+H]+ 436.4
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[N:3]=[N:2]1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>C(OCC)(=O)C>[CH2:18]([O:11][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[NH:1][N:2]=[N:3][C:4]=2[CH:9]=1)=[O:12])[CH3:19]
Reactant: CCO
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2[nH]nnc2c1
Yield: 86 %

Procedure:
A suspension of 1H-benzotriazole-5-carboxylic acid in ethanol (50 ml, excess) was gently refluxed overnight in the presence of conc. sulphuric acid (0.5 ml), by which time TLC (A) indicated complete reaction. Ethanol was removed in vacuo to afford an aqueous residue that was dissolved in ethyl acetate (30 ml) and extracted with sodium chloride solution (4×20 ml). The organic layer was dried over sodium sulphate and removal of solvent in vacuo afforded the pure ester [24] in 86% yield. Rf (A) 0.75; δH(400 MHz; DMSO-d6) 1.36 (3H, t, CH3) 4.36 (2H, q, CH2) 7.94 (2H, br s, BT) 8.59 (1H, br s, BT) 16.03 (1H, s, NH); m/z (EI−HR) 191.07023 [(M) calc. for C9H9N3O2 191.06948].
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:48][C:49]1[C:54]([NH2:55])=[CH:53][CH:52]=[CH:51][N:50]=1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([NH:55][C:54]4[C:49]([CH3:48])=[N:50][CH:51]=[CH:52][CH:53]=4)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:3])([CH3:4])[CH3:5]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: Cc1ncccc1N
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)Nc2cccnc2C)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 2-methyl-pyridin-3-ylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C41H48Cl2N7O3 [(M+H)+] 756.319, observed 756.3195.
Reaction SMILES: Cl.C[O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([OH:15])=[C:10]([F:16])[CH:9]=1)[NH2:6].[CH:18]1([N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](O)=[O:34])=[CH:32][C:27]=3[N:26]=[C:25]2[C:36]2[CH:40]=[CH:39][O:38][CH:37]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33]([NH:6][CH:5]([CH2:7][C:8]4[CH:13]=[C:12]([F:14])[C:11]([OH:15])=[C:10]([F:16])[CH:9]=4)[C:4]([OH:3])=[O:17])=[O:34])=[CH:32][C:27]=3[N:26]=[C:25]2[C:36]2[CH:40]=[CH:39][O:38][CH:37]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COC(=O)[C@@H](N)Cc1cc(F)c(O)c(F)c1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Agent: Cl
Product: O=C(NC(Cc1cc(F)c(O)c(F)c1)C(=O)O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
Racemic 3,5-difluorotyrosine methyl ester hydrochloride (example 119) was coupled to the carboxylic acid of example 2 in the usual manner and saponified to give the title compound of example 123.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:48][C@H:49]1[CH2:55][CH2:54][CH2:53][CH2:52][N:51]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[CH3:62])[C:50]1=[O:63]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:11])[NH:48][C@H:49]1[CH2:55][CH2:54][CH2:53][CH2:52][N:51]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[CH3:62])[C:50]1=[O:63])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: Cc1ccccc1N1CCCC[C@H](N)C1=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(c4ccccc4C)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((S)-2-oxo-1-o-tolylazepan-3-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (45 mg, 0.080 mmol) and Intermediate 69 (27 mg, 0.080 mmol) to give a white solid (35 mg, 57% yield). Anal. Calcd. for C44H54N4O6S m/z 766.7. found: 767.4 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.38-6.86 (m, 14H), 5.38-5.23 (m, 1H), 5.19-5.07 (m, 1H), 5.04-4.90 (m, 1H), 4.82-4.66 (m, 1H), 4.14 (s, 3H), 4.04-3.83 (m, 1H), 3.68 (s, 3H), 3.59-3.46 (m, 1H), 3.31 (dd, J=15.0, 4.9 Hz, 1H), 3.10 (dd, J=24.7, 11.2 Hz, 1H), 2.95-2.63 (m, 4H), 2.53-2.26 (m, 3H), 2.19 and 2.13 (2s, 3H), 2.07-1.92 (m, 3H), 1.91-1.42 (m, 12H), 1.44-1.27 (m, 1H).