Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2].N1C=CN=C1.[Si:60](Cl)([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.2 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-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 (Example 2, 3.01 g) in dry methylene chloride (70 ml) was added an excess of imidazole (809 mg) followed by tert-butyldimethylsilyl chloride (716 mg). After 3 days of stirring at room temperature, the mixture was diluted with ethyl acetate which in turn was washed with 1N HCl, saturated sodium bicarbonate and brine, dried over magnesium sulfate and purified by flash chromatography (ethyl acetate:hexane (1:3)) to give the title compound (941 mg). 1H NMR consistent with the desired structure.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[C@:10]([C:14](Cl)=[O:15])([CH2:11]2)[C@H:9]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:30][C:31]([F:47])([F:46])[C:32]1[CH:33]=[C:34]([C@@H:42]([NH:44][CH3:45])[CH3:43])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1>C(=O)(O)[O-].[Na+]>[F:30][C:31]([F:46])([F:47])[C:32]1[CH:33]=[C:34]([C@@H:42]([N:44]([CH3:45])[C:14]([C@:10]23[CH2:11][CH:12]2[CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:9]3[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH3:43])[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1
Reactant: O=C(Cl)[C@]12CC1CN(Cc1ccccc1)[C@@H]2c1ccccc1
Reactant: CN[C@@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: C[C@@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(C)C(=O)[C@]12CC1CN(Cc1ccccc1)[C@@H]2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.3 %

Procedure:
To racemic Intermediate 40, one enantiomer being (1R,2R)-3-benzyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-1-carbonyl chloride (0.17 g, 0.56 mmol) in MC (5 mL) was added triethylamine (0.23 mL, 1.7 mmol) and (S)-1-(3,5-bis(trifluoromethyl)phenyl)-N-methylethanamine 0.15 g, 0.56 mmol) in MC (1 mL). The reaction was allowed to stir at room temperature overnight. The reaction was diluted with saturated sodium bicarbonate solution and the phases separated. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to an oil. This material was flash chromatographed on silica using a gradient of 5 to 10% EtOAc/Hexanes to afford the title compound (0.056 g, 18% yield).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[N:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[C:9]([CH3:29])=[C:8]([C:30]([O:32]CC)=[CH2:31])[C:7]2=[O:35])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C(OCC)(=O)C.ClCCl.C([O-])(O)=O.[Na+]>[C:30]([C:8]1[C:7](=[O:35])[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]2[N:12]=[C:13]([NH:16][C:17]3[N:22]=[CH:21][C:20]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)=[CH:19][CH:18]=3)[N:14]=[CH:15][C:10]=2[C:9]=1[CH3:29])(=[O:32])[CH3:31]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCCCC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCCCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
8-Cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (0.180 g, 0.379 mmol) was dissolved in ethyl acetate (10 mL) and 6 N HCl (10 mL) was added then the mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane and aqueous NaHCO3. The layers were separated and the organic layer was dried over MgSO4, filtered, and the solvent evaporated to give 6-acetyl-8-cyclopentyl-5-methyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid (0.120 g, 71.0%). 1H NMR δ (400 MHz, CDCl3) 8.78 (s, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.95 (s, 1H), 7.39 (m, 1H), 5.85 (m, 1H), 3.15 (m, 4H), 2.53 (s, 3H), 2.36 (s, 3H), 2.33 (m, 2H), 2.05 (m, 2H), 1.87 (m, 2H), 1.77-1.56 (m, 8H). MS (APCI); M++1: Calc'd, 447.2. Found 447.2. Anal. Calc'd for C25H30N6O2 0.35 H2O: C, 66.31; H, 6.83; N, 18.56. Found: C, 66.68; H, 6.76; N, 18.07.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[OH-].[K+].C(OCC)(=O)C>CN(C=O)C.O>[Br:1][CH2:2][CH2:3][CH2:4][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: BrCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: BrCCCn1ncc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
1,3-Dibromopropane (508 μl, 5.0 mmol)) was dissolved in 10 mL DMF and placed in a 100 mL flask. Indazole (592 mg, 5.0 mmol) and KOH (282 mg, 5.0 mmol) were added and the suspension was stirred overnight at room temperature. Ethyl acetate (50 mL) and water (50 mL) were added. Phases were separated and the aqueous phase was re-extracted with ethyl acetate (50 mL). The combined organic phases were washed with brine, dried over magnesium sulphate and evaporated to dryness to produce 751 mg of a yellow oil. Crude product was further purified by column chromatography (0-10% methanol:dichloromethane) to produce pure 22 (169 mg, 14%).
Reaction SMILES: C([Cl:4])(=O)C.C(O[C:10](=O)[N:11]([C@H:13]([C:15](=[O:46])[NH:16][C@@H:17]([CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[C:18]([N:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:21]1[C:29](=[O:39])[NH:30][C:31]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=1[F:38])=[O:19])[CH3:14])C)(C)(C)C>CO>[ClH:4].[F:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:31]=1[NH:30][C:29]([C@@H:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:28][N:20]1[C:18](=[O:19])[C@H:17]([CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[NH:16][C:15](=[O:46])[C@@H:13]([NH:11][CH3:10])[CH3:14])=[O:39]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1Cc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Solvent: CO
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1Cc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F)C1CCCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A solution of acetyl chloride (552 mg, 500 μL, 7.03 mmol, Eq: 24.2) in MeOH (2 mL) was added to a vial containing ((S)-1-{(S)-1-Cyclohexyl-2-[(S)-1-(2,6-di fluoro-phenylcarbamoyl)-1,3-dihydro-iso indol-2-yl]-2-oxo-ethylcarbamoyl}-ethyl)-methyl-carbamic acid tert-butyl ester (174 mg, 291 μmol, Eq: 1.00). The mixture was stirred at RT for 1 h. The solvent was evaporated and the resulting solid was redissolved in MeCN (3 mL) and water (1 mL). It was lyophilized to give (S)-2-[(S)-2-Cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-2,3-dihydro-1H-isoindole-1-carboxylic acid (2,6-difluoro-phenyl)-amide hydrochloride (148 mg) as a white powder, m/z=499 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:33]([CH3:34])=[CH:32][C:5]([CH2:6][C@@H:7]([CH2:11][C:12](=[O:31])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:15][CH2:14]2)[C:8](O)=[O:9])=[CH:4][C:3]=1[Cl:35].[O:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1>>[NH2:1][C:2]1[C:33]([CH3:34])=[CH:32][C:5]([CH2:6][C@@H:7]([CH2:11][C:12]([N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:17][CH2:18]2)=[O:31])[C:8]([N:45]2[CH2:46][CH2:47][N:42]([CH:39]3[CH2:40][CH2:41][O:36][CH2:37][CH2:38]3)[CH2:43][CH2:44]2)=[O:9])=[CH:4][C:3]=1[Cl:35]
Reactant: Cc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(Cl)c1N
Reactant: C1CN(C2CCOCC2)CCN1
Product: Cc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(Cl)c1N

Procedure:
Prepared analogously to Example 7i from 70 mg (0.14 mmol) (S)-2-(4-amino-3-chloro-5-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid and 27 mg (0.16 mmol) 1-(tetrahydropyran-4-yl)-piperazine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:19](O)=[O:20])[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[OH:45][C@@H:46]1[CH2:50][CH2:49][NH:48][CH2:47]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:45][C@@H:46]1[CH2:50][CH2:49][N:48]([C:19]([C:8]2[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[CH:9]=2)=[O:20])[CH2:47]1
Reactant: O[C@@H]1CCNC1
Reactant: CCOC(=O)c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc(C(=O)N2CC[C@@H](O)C2)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(ethoxycarbonyl)-4′-methylbiphenyl-3-carboxylic acid (1.50 g, 5.28 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.0 g, 10 mmol), 1-hydroxybenzotriazole hydrate (0.404 g, 2.64 mmol), and CH2Cl2 (30 mL) were added (R)-3-hydroxypyrrolidine (0.92 g, 10 mmol) and N,N-diisopropylethylamine (1.8 mL, 10 mmol). The mixture was stirred at room temperature overnight, and then diluted with CH2Cl2 (100 mL), washed with aq. NaHCO3, brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column (100% EtOAc) to afford a white foam. LC-MS: 354.2 [M+1]+; 1H NMR (400 MHz, CDCl3): 8.32 (s, 1H), 8.16 and 8.12 (bs, 1H), 7.92 (m, 1H), 7.53 (d, 2H, J=7.6 Hz), 7.28 (d, 2H, J=8.4 Hz), 4.63 and 4.49 (bs, 1H), 4.41 (q, 2H, J=7.2 Hz), 3.95-3.40 (m, 4H), 2.41 (s, 3H), 2.20-1.90 (m, 2H), 1.41 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:15][C:16]([OH:18])=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH3:19][N:20](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].C[NH3+].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:19][NH:20][C:16](=[O:18])[CH2:15][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOC(=O)c1cc2ccccc2n1CC(=O)O
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccccc2n1CC(=O)NC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-(2-(ethoxycarbonyl)-1H-indol-1-yl)acetic acid (3.78 g), HATU (6.98 g), methylammonium chloride, and Hunig's base (6.33 mL) in DMF (77 mL) was stirred at room temperature for 24 hr. The reaction was worked up by the addition of water and the aqueous phase was extracted with EtOAc (2×65 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by CombiFlash (0-100% EtOAc/hexane) to afford the title compound as a yellowish solid.
Reaction SMILES: [C:1]([OH:16])(=[O:15])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].O.C(O)C.[CH:21]1[C:26]([NH:27]/[C:28](/[NH2:53])=[N:29]/[C:30]([NH2:52])=[N:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][N:38]=[C:39](/[N:41]=[C:42](\[NH:44][C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)/[NH2:43])[NH2:40])=[CH:25][CH:24]=[C:23]([Cl:54])[CH:22]=1>O>[CH:46]1[C:45]([NH:44][C:42]([NH:41][C:39]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:30]([NH:29][C:28]([NH:27][C:26]2[CH:21]=[CH:22][C:23]([Cl:54])=[CH:24][CH:25]=2)=[NH:53])=[NH:52])=[NH:40])=[NH:43])=[CH:50][CH:49]=[C:48]([Cl:51])[CH:47]=1.[C:1]([O-:16])(=[O:15])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13]
Reactant: NC(=NCCCCCCN=C(N)/N=C(\N)Nc1ccc(Cl)cc1)/N=C(/N)Nc1ccc(Cl)cc1
Reactant: O=C(O)/C=C/CCCCCCCCC(=O)O
Solvent: CCO
Solvent: O
Product: N=C(NCCCCCCNC(=N)NC(=N)Nc1ccc(Cl)cc1)NC(=N)Nc1ccc(Cl)cc1
Product: O=C([O-])/C=C/CCCCCCCCC(=O)[O-]
Temperature: 4 °C

Procedure:
2,28 g of trans-traumatic acid (10 mmol) are suspended in 100 ml of a mixture water/ethanol 2: 1 at 4° C., 5,05 g of chlorhexidine base (10 mmol) are added and the mixture is kept under stirring at 4° C. for hours and then at 25° C. overnight. 200 ml of water are added and the mixture is concentrated under vacuum at the volume of about 100 ml and Finally again cooled to 4° C. The resulting precipitate is recovered by filtration, washed three times using 10 ml of cool water and finally dried under high vacuum.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:20]([O:24][C:25](SC1N=C(C)C=C(C)N=1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O.O1CCOCC1>[C:25]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:9][C:10]([OH:12])=[O:11])([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26]
Reactant: Cc1cc(C)nc(SC(=O)OC(C)(C)C)n1
Reactant: O=C(O)CNc1ccc(O)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N(CC(=O)O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To 33.4 g (0.2 mol) of p-hydroxyphenylglycine were added 110 ml of water, 42 ml (1.5 eq.) of triethylamine, 52.8 g (1.1 eq.) of S-t-butoxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine and 110 ml of dioxane, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was added 300 ml of water, and the mixture was extracted with 400 ml of ethyl acetate. The organic layer was extracted with 100 ml of a 5% aqueous solution of sodium hydrogencarbonate. The aqueous layers were combined, adjusted to pH 3 with 5N hydrochloric acid under ice-cooling and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of potassium hydrogensulfate and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was distilled off. The thus-obtained crystals were collected by filtration with ethyl acetate/hexane. Yield: 46.0 g (86.1%).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]3([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1>C(O)C.O1CCCCC1.[Pd]>[O:6]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([CH2:16][C:17]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:15])=[O:14])=[CH:11][CH:12]=1)[C:5]1[CH:26]=[CH:27][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(O)C1(CS(=O)(=O)c2ccc(Oc3ccc(Br)cc3)cc2)CCOCC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOCC1
Product: O=C(O)C1(CS(=O)(=O)c2ccc(Oc3ccccc3)cc2)CCOCC1
Yield: 100 %

Procedure:
A solution of 660 mg (1.45 mmol) of 4-[4-(4-bromophenoxy)phenylsulfonylmethyl]-tetrahydropyran-4 -carboxylic acid in 80% ethanol/tetrahydropyran (40 mL) was hydrogenated at atmospheric pressure for 14 hours using palladium on carbon catalyst, filtered over a celite pad washing with methylene chloride and concentrated in vacuo to afford 4-[4-phenoxyphenylsulfonylmethyl]-tetrahydropyran-4-carboxylic acid as a light orange solid (546 mg, 100%), which was taken directly into the next reaction without further purification: mp 162.5-165.3° C.; IR (KBr) 3431 (br), 1727 cm-1 ; 1HNMR (DMSO-d6) δ 1.67 (ddd, J=14.1, 10.0, 4.0 Hz, 2H), 1.95 (dm, J=14.1 Hz, 2H), 3.47 (mc, 2H), 3.65 (mc, 2H), 3.66 (s, 2H), 7.15 (d, J=8.8 Hz, 2H), 7.27 (t, J=7.4 Hz, 1H), 7.45 (t, J=7.5 Hz, 2H), 7.86 (d, J=7.9 Hz, 2H), 12.74 (s, 1H); 13C NMR (DMSO-d6) δ 32.88 (t), 42.26 (s), 61.75 (t), 63.26 (t), 117.64 (d), 120.11 (d), 125.03 (d), 130.04 (d), 130.39 (s), 134.69 (s), 154.69 (s), 161.53 (s), 174.39 (s); FABHRMS Calcd for C19H21SO6 (M+ +H): 377.1059. Found: 378.1064. Anal. Calcd. for C19H20SO6.0.75H2O: C, 58.52; H, 5.56. Found: C, 58.54; H, 5.19.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:9]2[N:10]=[C:11]([CH2:13][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[NH:12][C:8]=2[CH:7]=[C:6]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[C:35]([C:42]([F:45])([F:44])[F:43])[CH:34]=2)[N:5]=1)#[N:3].[Cl:46][CH2:47][CH:48]=O.N12CCCN=C1CCCCC2.C(O)C>C1COCC1>[Cl:46][CH2:47][CH:48]=[CH:13][C:11]1[NH:12][C:8]2[CH:7]=[C:6]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[C:35]([C:42]([F:44])([F:45])[F:43])[CH:34]=3)[N:5]=[C:4]([C:2]#[N:3])[C:9]=2[N:10]=1
Reactant: O=CCCl
Reactant: CCOc1ccc(-c2cc3[nH]c(C[P+](c4ccccc4)(c4ccccc4)c4ccccc4)nc3c(C#N)n2)cc1C(F)(F)F
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOc1ccc(-c2cc3[nH]c(C=CCCl)nc3c(C#N)n2)cc1C(F)(F)F

Procedure:
A solution of [4-cyano-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridin-2-ylmethyl]-triphenyl-phosphonium chloride (167.2 mg, 0.26 mmol), chloroacetaldehyde (50% in water) (32,6 mg, 0.41 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (62.4 mg, 0.41 mmol) was dissolved in a 1:1 mixture of THF:ethanol (4 ml) at room temperature overnight. The mixture was concentrated and purified on preparative HPLC to afford the title compound. MS m/z 407.5 (m+1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([N:11]=[C:12]=[O:13])[CH3:10].C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21]CC)=O)C.CC[O-].[Na+]>C1COCC1.C(O)C>[CH2:27]([O:26][C:24]([C:18]1[C:19](=[O:21])[N:11]([CH2:9][CH3:10])[C:12](=[O:13])[N:6]([C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[CH:17]=1)=[O:25])[CH3:28]
Reactant: Nc1ccc(F)cc1
Reactant: CCN=C=O
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c(=O)n(CC)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a solution of 4-fluoroaniline (1.0 g, 9.01 mmol) in THF (20 mL) at 0° C., was slowly added ethyl isocyanate (0.70 g, 10.0 mmol). After stirring 30 min. at 0° C., the solution was warmed to rt and the solvent was removed under vacuum. To the residue was added ethanol (30 mL), diethyl ethoxymethylenemalonate (1.95 g, 9.01 mmol) and 21% NaOEt in ethanol (2.92 mL, 9.01 mmol)) and the reaction stirred 48 h at rt. The solvent was removed under vacuum and cold conc. HCl was added to pH 6. The aqueous layer was removed under vacuum and the solids were crystallized from ethyl acetate and hexanes. 3-Ethyl-1-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester isomer was isolated in 25% yield. 1H NMR (CDCl3) δ: 8.32 (s, 1H), 7.20-7.14 (m, 4H), 4.35 (q, 2H, J=7.1 Hz), 3.95 (q, 2H, J=7.2 Hz), 1.42 (t, 3H, J=7.2 Hz), 1.36 (t, 3H, J=7.2 Hz).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([CH:15]=[C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH:17]=3)[C:13]#N)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:28]([Mg]Cl)([CH3:30])[CH3:29].S(=O)(=O)(O)[OH:34]>C1COCC1.C(OCC)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([C:13](=[O:34])[CH:28]([CH3:30])[CH3:29])[CH:15]=[C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(COc2cc(C#N)cc(-c3ccc4c(c3)OCO4)c2)cc1
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(COc2cc(C(=O)C(C)C)cc(-c3ccc4c(c3)OCO4)c2)cc1
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 3-benzo[1,3]dioxol-5-yl-5-(4-methoxy-benzyloxy)-benzonitrile (500 mg) in anhydrous THF (10 mL) were added a solution of isopropylmagnesium chloride (2.1 mL of 2 M solution in diethyl ether) and catalytic amount of cuprous bromide (4 mg). The resulting reaction mixture was refluxed for 2 h. After it was cooled down, 10% sulfuric acid (5 mL) was added and stirring was continued for 30 min at room temperature. Then the reaction mixture was diluted with diethyl ether, washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 358 mg of the title compound (64% yield). HRMS calcd for C25H24O5 [M+H]+ 405.1697, observed 405.1698.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:14])[CH3:5].C(=O)([O-])[O-].[Na+].[Na+].[Cl:22][CH2:23][C:24](Cl)=[O:25]>C1C=CC=CC=1>[CH3:1][O:2][C:3]([CH:4]([N:6]([C:24](=[O:25])[CH2:23][Cl:22])[C:7]1[C:8]([CH3:14])=[CH:9][CH:10]=[CH:11][C:12]=1[CH3:13])[CH3:5])=[O:15]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)C(C)Nc1c(C)cccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)C(C)N(C(=O)CCl)c1c(C)cccc1C
Temperature: 25 °C

Procedure:
990.3 g (= 4.76 g-moles) of α-(2,6-dimethylanilino)-propionic acid methyl ester is mixed with 605 g (= 5.7 g-moles) of sodium carbonate in 2.5 liters of benzene (absolute). An amount of 455 ml (= 5.7 g-moles) of monochloroacetyl chloride is then added dropwise and sufficiently slowly to ensure that a temperature of 30°-35° in the reaction mixture is not exceeded. After stirring has been maintained overnight at room temperature, the mixture is filtered off, and the filtrate concentrated in a rotary evaporator at ca. 50°. The resulting residue is recrystallised from ligroin (boiling range 65°-90° ). The yield obtained is 1132 g (= 83.8% of theory) of final product, M.P. 92°-94° (compound No. 3).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].ClC(OCC(C)C)=O.[CH2:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]([OH:37])[CH3:36])[CH3:28].Cl>C1COCC1.C(N(CC)CC)C>[CH2:27]([N:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]([OH:37])[CH3:36])[C:15](=[O:17])[CH2:14][CH2:13][C:12](=[O:18])[C:9]1[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=1)[CH3:28]
Reactant: CCNCCCCCC(C)O
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CCCCCC(C)O)C(=O)CCC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: -8 °C
Reaction time: 1.5 h
Yield: 48.5 %

Procedure:
A stirred solution of 4-((methanesulfonyl)amino)-γ-oxobenzenebutanoic acid (as described in EP 164 865) (0.49 g, 1.8 mmol) in THF (15 ml), under nitrogen, was treated with triethylamine (0.28 ml), cooled to -8° C. and treated during 5 minutes with isobutyl chloroformate (0.26 ml, 2.04 mmol). This mixture was kept at -5° to -8° C. for 90 minutes and then treated during 30 minutes with a solution of the product from Step III (0.31 g, 1.95 mmol) and triethyl amine (0.28 ml) in THF (10 ml). The mixture was kept at -8° C. for 2 hours and then poured into 1N HCl (19.2 ml). The product was extracted with EtOAc; the extract was washed successively with water, aqueous NaHCO3, water and brine; dried (MgSO4) and concentrated. The residue was crystallized frown EtOAc-hexane to give 0.36 g (48.6%) of N-ethyl-N-(6-hydroxyheptyl)-γ-oxo-4-((methanesulfonyl)amino)benzenebutanamide, mp 78°-80° C.