Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].[CH2:20]([C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=[O:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O1CCCC1>[CH3:13][O:14][CH:15]([CH:34]([OH:35])[C:33]1[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:16]([O:18][CH3:19])=[O:17]
Reactant: CCCCCCCCCCCCc1ccccc1C=O
Reactant: COCC(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCCCCCCCCc1ccccc1C(O)C(OC)C(=O)OC
Reaction time: 0.25 h

Procedure:
To a solution of di-i-propylamine (0.77 ml, 5 mmoles) in tetrahydrofuran (10 ml) at -78° C. was added n-butyl lithium (2.1 ml, 5.5 mmoles) under argon atmosphere. After 15 minutes, methyl methoxyacetate (0.52 g, 5 mmoles) in tetrahydrofuran (2 ml) was added dropwise, with stirring. The resulting enolate solution was stirred at -78° C. for 45 minutes. A solution of 2-dodecylbenzaldehyde (1.65 g, 6 mmoles) in tetrahydrofuran (2 ml) was added. The resulting light-blue mixture became a suspension after 1.5 hours. The reaction mixture was quenched with saturated ammonium chloride solution, diluted with ether and ice-water. The aqueous phase was extracted with ether. The combined organic extract was washed with saturated sodium chloride solution, dried over magnesium sulfate, and evaporated to give the product, which was purified by flash column chromatography (silica, 15% ethyl acetate/hexane). The fractions were pooled to give 620 mg (33%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:14]2[NH:15][C:16]([C:18]3[C:19](=[O:34])[NH:20][CH:21]=[CH:22][C:23]=3[NH:24][CH2:25][C@@H:26]([OH:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:17][C:13]=2[CH:12]=[CH:11][CH:10]=1.[C:35]1([CH2:41][C:42](Cl)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N>C1COCC1>[OH:33][C@@H:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:25][NH:24][C:23]1[CH:22]=[CH:21][NH:20][C:19](=[O:34])[C:18]=1[C:16]1[NH:15][C:14]2[C:9]([NH:8][C:42](=[O:43])[CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:10][CH:11]=[CH:12][C:13]=2[N:17]=1
Reactant: Nc1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Reactant: O=C(Cl)Cc1ccccc1
Agent: N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)Nc1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Temperature: 25 °C
Yield: 42.7 %

Procedure:
Triethylamine (0.058 g, 0.416 mmol) was added to a solution of 3-(7-amino-1H-benzoimidazol-2-yl)-4-((S)-2-hydroxy-2-phenyl-ethylamino)-1H-pyridin-2-one (0.060 g, 0.166 mmol) (Prepared according to the general method for the intermediates of formula II and III above) and phenylacetyl chloride (0.051 g 0.32 mmol) in THF (2 ml) and the reaction stirred at room temperature. After 20 hours methanolic ammonia was added (5 ml) and the reaction stirred for a further 20 hours. The reaction mixture was concentrated under reduced pressure and the crude solid washed with acetonitrile water (1:1; 10 ml) to give the desired product (0.034 g; 43%).
Reaction SMILES: C1(C)C(C)=CC=CC=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]([OH:29])[CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:15][C:14]=1[NH:30][C:31](=[O:47])[CH2:32][CH:33]1[C:46]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[O:40][C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2)([CH3:12])([CH3:11])[CH3:10].[C:48]1(=[O:54])[O:53][C:51](=[O:52])[CH2:50][CH2:49]1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(OCC)C>[C:48]([O:29][CH:21]([CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]([CH3:12])([CH3:10])[CH3:11])=[C:14]([NH:30][C:31](=[O:47])[CH2:32][CH:33]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:39]=3[O:40][C:41]3[C:46]2=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:15]=1)[CH2:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)(=[O:54])[CH2:49][CH2:50][C:51]([OH:53])=[O:52]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)c1ccc(CCC(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(CCC(CC2CCCCC2)OC(=O)CCC(=O)O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 125 °C
Reaction time: 9 h
Yield: 83.3 %

Procedure:
5 ml of a xylene solution containing 74 mg (0.14 mmol) of N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 12), 15 mg (0.15 mmol) of succinic anhydride, 18 mg (0.15 mmol) of 4-(N,N-dimethylamino)pyridine and 112 mg (1.41 mmol) of pyridine were stirred for 9 hours at 125° C. At the end of this time, the reaction mixture was allowed to return to room temperature. The reaction solution was then diluted with diethyl ether, and washed with dilute aqueous hydrochloric acid and then with water. The solvent was then removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 20 g of silica gel. Elution using a gradient elution method, with mixtures of methylene chloride and methanol in ratios ranging from 100:5 to 10:1 by volume as the eluent, afforded 73 mg (yield 84%) of the title compound as a foam-like substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16]OS(C)(=O)=O)[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[C:28]([F:29])=[CH:27][C:26]([F:30])=[CH:25][C:24]=1[CH2:31][C:32](=[O:34])[CH3:33].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CS(C)=O.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16][CH:31]([C:24]1[CH:25]=[C:26]([F:30])[CH:27]=[C:28]([F:29])[C:23]=1[F:22])[C:32](=[O:34])[CH3:33])[C:10]([O:12][CH:13]([CH3:14])[CH3:15])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)OC(=O)C(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: CC(=O)Cc1cc(F)cc(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)C(CC(NC(=O)OC(C)(C)C)C(=O)OC(C)C)c1cc(F)cc(F)c1F
Reaction time: 30 h
Yield: 59.7 %

Procedure:
To a solution of 2 (10.98 g, 33.7 mmol) in THF (50 mL) was added TEA (4.8 g, 47.4 mmol) in portions at 15-20° C. The mixture was stirred for 30 h. After the reaction was complete, the solution was concentrated to give crude 7. To a solution of 44 (6.3 g, 33.7 mmol) and Cs2CO3 (5.0 g, 15.3 mmol) in DMSO (35 mL) was added slowly crude 7 in DMSO (35 mL) over 30 min at 15-20° C. The mixture was stirred for 1 h. After the reaction was complete, the mixture was partitioned with water and MTBE (50 mL) and extracted twice by MTBE. The combined organic layer was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (5-10% EtOAc/PE) to 45 (8.4 g, 60% yield). 1H NMR (DMSO-d6, 400 MHz): δ 6.77 (d, 1H), 6.59 (d, 1H), 5.11 (m, 1H), 4.93-4.89 (m, 1H), 4.12 (s, 2H), 2.66 (d, 1H), 2.05-2.01 (d, 3H), 1.38 (m, 9H), 1.18-1.15 (m, 6H); MS (ESI) m/e [M+H]+: 418.18.
Reaction SMILES: C(Cl)(Cl)Cl.[SH:5][C:6]1[C:7]([NH:16][C:17]([C:19]2([CH2:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>N1C=CC=CC=1>[CH2:27]([CH:26]([CH2:29][CH3:30])[CH2:25][C:19]1([C:17]([NH:16][C:7]2[C:6]([S:5][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])=[CH:15][C:14]3[C:9]([CH:8]=2)=[CH:10][CH:11]=[CH:12][CH:13]=3)=[O:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)[CH3:28]
Reactant: CC(C)C(=O)Cl
Reactant: CCC(CC)CC1(C(=O)Nc2cc3ccccc3cc2S)CCCCC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCC(CC)CC1(C(=O)Nc2cc3ccccc3cc2SC(=O)C(C)C)CCCCC1
Reaction time: 1 h

Procedure:
To a chloroform solution of the product obtained in step B) are added 1.05 mol equivalents of isobutyryl chloride and 2.5 mol equivalents of pyridine at room temperature. The mixture is stirred for 1 hour, concentrated and then n-hexane is added. The solids are filtered off and the filtrate is concentrated. The remaining residue is purified by silica gel column chromatography to obtain the desired title compound.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C@H:10]1[O:15][C@@H:14]([CH3:16])[CH2:13][N:12]([C:17]2[C:26]([CH:27]=[O:28])=[CH:25][C:20]3[C:21]([OH:24])=[N:22][O:23][C:19]=3[C:18]=2[F:29])[CH2:11]1>>[CH2:1]([O:24][C:21]1[C:20]2[CH:25]=[C:26]([CH:27]=[O:28])[C:17]([N:12]3[CH2:13][C@H:14]([CH3:16])[O:15][C@H:10]([CH3:9])[CH2:11]3)=[C:18]([F:29])[C:19]=2[O:23][N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(O)noc3c2F)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(C=O)cc3c(OCc4ccccc4)noc3c2F)C[C@H](C)O1

Procedure:
Benzyl bromide and 6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-3-hydroxy-1,2-benzisoxazole-5-carbaldehyde (Intermediate 556) were reacted using a method similar to the one described for the synthesis of Intermediate 557, providing the title product, along with a by-product, 2-benzyl-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-3-oxo-2,3-dihydro-1,2-benzoxazole-5-carbaldehyde. The mixture was used in the next step with out further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[C:4](O)=[O:5].[NH2:10][NH:11][C:12]([NH:14][NH2:15])=[S:13]>>[NH2:15][N:14]1[C:4](=[O:5])[C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])=[N:10][N:11]=[C:12]1[SH:13]
Reactant: NNC(=S)NN
Reactant: CC(C)(C)C(=O)C(=O)O
Product: CC(C)(C)c1nnc(S)n(N)c1=O

Procedure:
Trimethylpyruvic acid of formula (VI) can be subjected to a condensation reaction with 1 to 1.5 moles of thiocarbohydrazide (NH2 --NH--CS--NH--NH2) in aqueous solution containing a hydrogen halide acid, at a temperature between 20° and 100° C., to give 4-amino-6-tert.-butyl-3-mercapto-1,2,4-triazin-5(4H)-one of formula (VII).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[CH:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[C:4]([Cl:25])[N:3]=1.[O:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1>>[Cl:25][C:4]1[CH:5]=[C:6]([C:8]2[N:12]3[CH:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:7]=[C:2]([C:28]2[CH:29]=[CH:30][O:26][CH:27]=2)[N:3]=1
Reactant: OC1CCCC(Nc2ccc3ncc(-c4cc(Cl)nc(Cl)c4)n3c2)C1
Reactant: OB(O)c1ccoc1
Product: OC1CCCC(Nc2ccc3ncc(-c4cc(Cl)nc(-c5ccoc5)c4)n3c2)C1

Procedure:
The title compound is prepared from (1SR,3RS)-3-[3-(2,6-dichloro-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol (Intermediate S) and 3-furyl boronic acid using a procedure analogous to that described in Example 2.3.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([NH2:12])[CH:6]=1)(=[O:3])[CH3:2].C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18](=[O:19])[C:17](=[CH:16][NH:12][C:7]1[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][C:8]=1[F:11])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(=O)Nc1ccc(F)c(N)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1cc(NC(C)=O)ccc1F)C(=O)OCC
Temperature: 25 °C
Yield: 86.1 %

Procedure:
A mixture of 1.9 g (0.0113 mol) of 4-(N-acetylamino)-2-amino-1-fluorobenzene, 2.6 ml (2.78 g/0.0129 mol) of diethyl ethoxymethylenemalonate, and 4 ml of toluene is stirred at reflux for three hours, then allowed to cool to ambient temperature. The resulting precipitate is triturated with ether to give 3.29 g (84%) of title compound:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[N:20][N:19]=[N:18]2)=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1.C(OC([NH:29][C@@H:30]([C:35](O)=[O:36])[CH2:31][CH:32]1[CH2:34][CH2:33]1)=O)(C)(C)C.Cl.CCOC(C)=O>>[CH:32]1([CH2:31][C@H:30]([C:35]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([NH:8][CH2:7][C:6]2[CH:16]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N:17]2[CH:21]=[N:20][N:19]=[N:18]2)=[O:15])=[O:36])[NH2:29])[CH2:34][CH2:33]1
Reactant: O=C(NCc1cc(F)ccc1-n1cnnn1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CC1)C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H](CC1CC1)C(=O)N1CCC[C@H]1C(=O)NCc1cc(F)ccc1-n1cnnn1

Procedure:
The title compound was prepared from N-[5-fluoro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide and N-(tert-butoxycarbonyl)-3-cyclopropyl-D-alanine (Example 31, Step C) followed by deprotection with HCl-EtOAc essentially according to the procedures described in Example 31, Steps D and E. HPLC RT=0.93 min (Method B); LCMS (M+H): 402; 1H NMR (400 MHz, DMSO-d6): δ 9.86 (s, 1H), 8.66 (t, J=6 Hz, 1H), 8.22–8.35 (m, 2H), 7.64–7.67 (m, 1H), 7.38–7.39 (m, 2H), 4.18–4.30 (m, 1H), 4.00–4.22 (m, 3H), 3.73–3.82 (m, 1H), 3.52–3.58 (m, 1H), 2.0–2.13 (m, 1H), 1.77–1.94 (m, 3H), 1.65–1.74 (m, 1H), 1.52–1.61 (m, 1H), 0.77–0.85 (m, 1H), 0.44–0.48 (m, 2H), 0.05–0.17 (m, 2H).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl.[NH2:19][CH2:20][C:21](=[O:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>ClCCl>[C:23]1([CH2:22][C:21](=[O:29])[CH2:20][NH:19][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCC(=O)Cc1ccccc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1ccncc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 89.7 %

Procedure:
Isonicotinoyl chloride hydrochloride (1.44 g, 8.09 mmol) was stirred in dry dichloromethane (20 ml) and triethylamine (4.0 ml, 2.9 g, 20 mmol) was added. The mixture was stirred at 25° C. for 5-10 minutes, then cooled in an ice bath. 1-Amino-3-phenyl-2-propanone hydrochloride (1.00 g, 5.39 mmol) was added in portions over 4 minutes. The reaction was stirred 0.5 hour while warming to 25° C., then 0.5 hour at 25° C. Water (5-10 ml) was added and the mixture was stirred 5 minutes before being extracted with ethyl acetate (75 ml). The organic layer was washed with saturated aqueous sodium bicabonate (2×35 ml) and saturated aqueous sodium chloride (35 ml), dried (sodium sulfate), decanted, and evaporated. The residue was purified by flash column chromatography on silica gel (50 g) eluted with 5% isopropanol in dichloromethane, yielding N-(3-phenyl-2-oxopropyl)isonicotinamide (1.23 g, 89% yield) as an orange oil which crystallized (m.p. 85°-86° C.) upon standing. Recrystallization of a portion of this material from toluene raised the m.p. to 86°-88° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[Cl:21][C:22]1[C:27]2[NH:28][C:29]([CH3:31])=[N:30][C:26]=2[CH:25]=[C:24]([O:32][C:33]2[CH:38]=[C:37](Cl)[N:36]=[CH:35][N:34]=2)[CH:23]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[Cl:21][C:22]1[C:27]2[NH:28][C:29]([CH3:31])=[N:30][C:26]=2[CH:25]=[C:24]([O:32][C:33]2[N:34]=[CH:35][N:36]=[C:37]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:38]=2)[CH:23]=1
Reactant: Cc1nc2cc(Oc3cc(Cl)ncn3)cc(Cl)c2[nH]1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(Cl)c5[nH]c(C)nc5c4)ncn3)CC1)C(=O)N2

Procedure:
100 mg (0.36 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 110 mg (0.37 mmol) 7-chloro-5-(6-chloropyrimidin-4-yloxy)-2-methyl-1H-benzo[d]-imidazole and 0.14 mL (0.81 mmol) DIPEA in 2.0 mL DMF were stirred for 3 h at RT and 4 h at 40° C. The reaction mixture was mixed with water. The precipitate formed was suction filtered, washed and dried. The substance was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH2:9][CH2:10][CH2:11][C:12]([N:14]2[C@@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][O:16][C:15]2=O)=[O:13])=[CH:4][CH:3]=1.FC1C=CC([C@@H](O)CCCC(N2[C@@H](C3C=CC=CC=3)COC2=O)=[O:39])=CC=1.[O-]S([O-])(=O)=O.[Mg+2]>C(O)(C)C>[O:39]=[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:19]1[C@H:18]1[CH2:17][O:16][CH2:15][N:14]1[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:26]
Reactant: O=C(CCCC(=O)N1C(=O)OC[C@@H]1c1ccccc1)c1ccc(F)cc1
Reactant: O=C(CCC[C@H](O)c1ccc(F)cc1)N1C(=O)OC[C@@H]1c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)O
Product: O=C(CCCC(=O)N1COC[C@@H]1C1C=CC=CC1=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Improved ADH-LK variants for the reduction of (S)-1-(4-Fluoro-phenyl)-5-(2-oxo-4-phenyl-oxazolidin-3-yl)-pentane-1,5-dione to (4S)-3-[(5S)-5-(4-Fluoro-phenyl)-5-hydroxy-pentanoyl]-4-phenyl-oxazolidin-2-one were analyzed in small scale chemical reactions. In a glass vial with a teflon stirring bar, 500 mg (S)-1-(4-Fluoro-phenyl)-5-(2-oxo-4-phenyl-oxazolidin-3-yl)-pentane-1,5-dione, 100 mg KRED variant, 0.5 mg Na-NADP (Oriental Yeast), 2.5 ml isopropyl alcohol, and 2.5 ml 100 mM triethanolamine(chloride) buffer, pH 7.0, 2 mM MgSO4 was mixed and stirred overnight at 25° C. Reaction samples were analyzed by the method of Example 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:22]([O:24]CC)=[O:23])=[N:10]2)=[CH:5][CH:4]=1.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:22]([OH:24])=[O:23])=[N:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc(-c2ccc(SC)cc2)n(-c2ccc(OC)cc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-n2nc(C(=O)O)cc2-c2ccc(SC)cc2)cc1
Yield: 93.4 %

Procedure:
A mixture of ethyl 1-(4-methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazole-3-carboxylate (10.2 g) and potassium hydroxide (3.7 g) in methanol (60 ml) was refluxed for 30 minutes. The solvent was evaporated, and the residue was dissolved in water and washed with toluene. The aqueous layer was acidified, and the precipitates were collected and washed with ethyl acetate to give crystals of 1-(4-methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazole-3-carboxylic acid (8.8 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH2:19][CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH:23]=2)=[N:6][C:7]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:10]=2[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:17][C:14]1[CH:15]=[CH:16][C:10]2[N:9]=[C:8]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=4)[N:6]=3)[NH:12][C:11]=2[CH:13]=1
Reactant: Cc1ccc2nc(-c3nc(C4=CCN(C(=O)OC(C)(C)C)CC4)cnc3N)[nH]c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2nc(-c3nc(C4=CCNCC4)cnc3N)[nH]c2c1

Procedure:
Tert-butyl 4-[5-amino-6-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (620 mg, 1.525 mmol) was stirred in DCM (20 mL) with TFA (4 mL) for 2 hours. The solvent was removed in vacuo and the residue taken up in EtOAc and washed with saturated aqueous Na2CO3. DCM was added and the resultant solid was collected by filtration and taken through to the next stage. MS (ES+) 307
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[C:8]([C:12]1[CH:13]=[C:14]([OH:18])C=[CH:16][CH:17]=1)([CH3:11])([CH3:10])[CH3:9].C1N2CN3CN(C2)CN1C3>O>[C:8]([C:12]1[CH:13]=[C:14]([OH:18])[C:2](=[CH:16][CH:17]=1)[CH:3]=[O:5])([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)c1cccc(O)c1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: CC(C)(C)c1ccc(C=O)c(O)c1
Temperature: 80 °C
Yield: 56 %

Procedure:
A five liter three-neck round bottom flask equipped with overhead mechanical stirrer and condenser was charged with trifluoroacetic acid (2.4 L). A mixture of 3-tert-butylphenol (412 g, 2.8 mole) and HMTA (424 g, 3.0 mole) was added portion-wise causing an exotherm. With cooling, the temperature was maintained under 80° C. The reaction was heated at 80° C. for one hour, then cooled, and water (2 L) added. After 0.5 hour additional water (4 L) was added and the mixture was extracted with ethyl acetate (6 L). The organic extract was washed with water and brine. The resulting organic phase was divided into 2 L volumes and each diluted with water (1 L), and solid NaHCO3 added until the mixture was neutralized. The organic phases were isolated and combined, dried over MgSO4, filtered and concentrated in vacuo yielding an oil. This oil was distilled at 95° C. (0.8 mm) yielding the desired salicylaldehyde as an oil (272.9 g, 56%) which was of sufficient purity to be used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[CH2:10][C:11](O)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[O:25]([NH2:27])[CH3:26].O>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH2:10][C:11]([NH:27][O:25][CH3:26])=[O:12])=[CH:17][CH:18]=1)#[N:23]
Reactant: CON
Reactant: N#Cc1ccc(CCC(CC(=O)O)c2cccc(C#N)c2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CONC(=O)CC(CCc1ccc(C#N)cc1)c1cccc(C#N)c1
Yield: 91.8 %

Procedure:
Part A. A solution of 3-(3-cyanophenyl)-5-(4-cyanophenyl)pentanoic acid (0.15 gm, 0.49 mmol), methoxylamine hydrochloride (0.041 gm, 0.54 mmol), 1-(3-dimethylaminopropyl)-3-ethhylcarbodiimide hydrochloride (0.14 gm, 0.73 mmol) and 4-dimethylaminopyridine (0.15 gm, 1.22 mmol) in 5 mLs DMF under a nitrogen atmosphere was stirred for 18 hrs. The reaction solution was poured into water and extracted with ethyl acetate. The combined organic layer was washed with 1 N HCl (2×), water, brine, dried over magnesium sulfate and concentrated to give the crude product as a colorless viscous oil. The product was purified by flash chromatography on silica gel (50 mLs) eluting methylene chloride:ethyl acetate (v:v, 60:40) to give 4-(cyano)-beta-(3-cyanophenyl)-N-methoxybenzene pentanamide as a colorless vicous oil 0.15 gm (91%) 1H NMR (CDCl3): 8.03(bs, 1H), 7.56-7.42(m, 6H), 7.15(d, 2H), 3.58(s, 3H), 3.28(m, 1H), 2.8-1.85(m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].O[CH2:11][CH:12]1[CH2:15][CH2:14][O:13]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH:12]2[CH2:15][CH2:14][O:13]2)=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: OCC1CCO1
Product: Fc1cc(OCC2CCO2)ccc1Br

Procedure:
The title compound was prepared from 4-bromo-3-fluorophenol and rac-2-hydroxymethyl-oxetane in analogy to Example 9c): MS (EI): 260 and 262 M+.