Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[NH2:3]/[C:4](=[N:25]\[OH:26])/[C:5]1[CH:24]=[CH:23][C:8]2[CH:9]=[C:10]([C:12]([NH:14][C@@H:15]3[CH:20]4[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]4)[CH2:16]3)=[O:13])[S:11][C:7]=2[CH:6]=1.[H-].[Na+].[C:29]1([CH2:35][C:36](OC)=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C=O)C.C1COCC1>[ClH:1].[N:17]12[CH2:18][CH2:19][CH:20]([CH2:21][CH2:22]1)[C@@H:15]([NH:14][C:12]([C:10]1[S:11][C:7]3[CH:6]=[C:5]([C:4]4[N:3]=[C:36]([CH2:35][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[O:26][N:25]=4)[CH:24]=[CH:23][C:8]=3[CH:9]=1)=[O:13])[CH2:16]2
Reactant: N/C(=N\O)c1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: COC(=O)Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(-c3noc(Cc4ccccc4)n3)cc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
110 mg (0.26 mmol) of 6-[amino(hydroxyimino)methyl]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride (Example 27A) are dissolved in 2 ml of DMF and 0.75 ml of THF. 250 mg of 4 Å molecular sieves are added, and the mixture is stirred at room temperature for 30 min. Addition of 31.2 mg (0.79 mmol) of sodium hydride (60% suspension in mineral oil) is followed by heating at 60° C. for 20 min and then cooling to room temperature. A solution of 110 μl (0.79 mmol) of methyl phenylacetate in 1 ml of THF is added, and the mixture is heated at 80° C. for 14 h. Addition of a further 20.8 mg (0.52 mmol) of sodium hydride (60% suspension in mineral oil) and 1.14 ml (7.91 mmol) of methyl phenylacetate in 1 ml of THF is followed by heating at 70° C. for a further 24 h. The reaction is stopped by adding water. Purification takes place by preparative HPLC. The product fractions are concentrated and, after addition of a 5:1 mixture of methanol and 4N hydrogen chloride in dioxane, again concentrated. Drying under high vacuum results in 4.1 mg (3% of theory) of the title compound.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:12]([Cl:13])=[C:11]2[C:7]([CH:8]=[C:9]([CH3:14])[NH:10]2)=[CH:6][CH:5]=1.Br[CH2:16][CH2:17][CH2:18][Cl:19]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:3][C:4]1[C:12]([Cl:13])=[C:11]2[C:7]([CH:8]=[C:9]([CH3:14])[N:10]2[CH2:16][CH2:17][CH2:18][Cl:19])=[CH:6][CH:5]=1
Reactant: ClCCCBr
Reactant: Cc1cc2ccc(Cl)c(Cl)c2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc2ccc(Cl)c(Cl)c2n1CCCCl

Procedure:
7.84 g of crushed sodium hydroxide, 190 ml of toluene, 7 g of 6,7-dichloro-2-methyl-1H-indole, 85 ml of toluene and 0.7 g of tetrabutylammonium hydrogensulphate are introduced under nitrogen. The mixture is heated at reflux for 30 minutes, then 14 ml of 1-bromo-3-chloropropane are added and reflux is maintained for 2 hours. The reaction medium is poured onto water and the aqueous phase is washed with toluene. Extraction is carried out with toluene and then the extract is washed with water and with a saturated NaCl solution. The extract is dried and evaporated to produce 11.3 g of the expected compound.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].O=[C:12]([CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[CH2:13][C:14](OCC)=[O:15]>>[OH:15][C:14]1[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=[C:12]([CH:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:20])[CH:13]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCOC(=O)CC(=O)C(C)c1ccccc1
Product: CC(c1ccccc1)c1cc(O)n(-c2cc(C#N)ccn2)n1
Yield: 40 %

Procedure:
The title compound was prepared in 40% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 3-oxo-4-phenylpentanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[CH2:11]([N:17]=[C:18]=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(Cl)Cl>[CH2:11]([NH:17][C:18](=[O:19])[NH:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCN=C=O
Reactant: N[C@@H](CO)c1ccccc1
Solvent: ClCCl
Product: CCCCCCNC(=O)N[C@@H](CO)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(2R)-2-amino-2-phenylethanol (960 mg) was dissolved in methylene chloride (20 ml) and cooled to 0° C. To the mixture was added hexyl isocyanate (1.0 ml) and the mixture was stirred for 30 minutes at 0° C. and then stirred for 1 hour at room temperature. The solution was washed with 1N hydrochloric acid and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure. The obtained crystal was washed with diethyl ether to give the title compound (930 mg) having the following physical data.
Reaction SMILES: ClCC(C1C=CC=CC=1C)=O.ClCC(C1C=CC=C(C)C=1)=O.[Cl:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)=[O:26].ClCC(C1C=CC=CC=1C)O.ClCC(C1C=CC=C(C)C=1)O>>[Cl:23][CH2:24][CH:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)[OH:26]
Reactant: Cc1ccc(C(=O)CCl)cc1
Agent: Cc1cccc(C(=O)CCl)c1
Agent: Cc1cccc(C(O)CCl)c1
Agent: Cc1ccccc1C(=O)CCl
Product: Cc1ccc(C(O)CCl)cc1

Procedure:
Cultivation, reaction and purification were carried out in the same way as described in Example 9 except that 2-chloro-1-(2'-methylphenyl) ethanone, 2-chloro-1-(3'-methylphenyl) ethanone, 2-chloro-1-(4'-methylphenyl) ethanone were used as substrate, and (-)-2-chloro-1-(2'-methylphenyl) ethanol, (-)-2-chloro-1-(3'-methylphenyl) ethanol, (-)-2-chloro-1-(4'-methylphenyl) ethanol were obtained. The yield, specific rotation and optical purity determined by high-performance liquid chromatography were shown in Table 6.
Reaction SMILES: [CH2:1]([C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8][CH2:7][CH:6]1[OH:10])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:1]([C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8][CH2:7][CH:6]1[O:10][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(C(=O)OCC)CCCC1O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC1(C(=O)OCC)CCCC1OC(=O)c1ccccc1
Reaction time: 12 h
Yield: 93.7 %

Procedure:
10.7 grams of ethyl 1-n-butyl-2-hydroxy-cyclopentane carboxylate obtained in Example 16 were diluted with 60 ml of methylene chloride. At room temperature and with magnetic stirring, 6.108 ml of pyridine was slowly added, then 8.876 ml of benzoyl chloride was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then the procedure as described in Example 23 was followed, to give 19.06 g of brown liquid. The brown liquid was purified through column chromatography to give a liquid with a purity, measured by GC, of 96.03%. Yield: 93.7%. MS: 318(M+), 273(M+—OCH2CH3), 261(M+−CH2CH2CH2CH3), 245(M+—CO2CH2CH3), 213, 197(M+—C6H5CO2), 105(base), 77.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[O:12][CH2:11][C:10]([C:16]([OH:18])=[O:17])=[CH:9][C:8]=3[C:7]=2[CH:19]=1>C(O)C.CN(C)C=O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[O:12][CH2:11][CH:10]([C:16]([OH:18])=[O:17])[CH2:9][C:8]=3[C:7]=2[CH:19]=1
Reactant: COc1ccc2ccc3c(c2c1)C=C(C(=O)O)CO3
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc2ccc3c(c2c1)CC(C(=O)O)CO3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The unsaturated acid obtained in Step A (750 mg:2.9 mmol) is solubilized in a mixture of ethanol/dimethylformamide (20 ml:3 ml) in the reactor of a Parr apparatus. After addition of the catalyst, 10% palladium-on-carbon (75 mg; 10% by weight), the whole is stirred at ambient temperature at a pressure of 45 psi for 4 hours. The solvents are removed; the residual oil is then precipitated and washed with diethyl ether.
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](=[O:17])[CH2:9][C:10](OC(C)(C)C)=O.BrC[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](=[O:17])[CH2:9][CH2:10][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccco1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: CCOC(=O)CCC(=O)c1ccco1
Reaction time: 0.17 h
Yield: 79 %

Procedure:
Sodium hydride (60% in oil, 629 mg) was added to a solution of tert-butyl 3-(2-furyl)-3-oxopropionate (3.01 g) in tetrahydrofuran (80 ml) at 0° C. and stirred for 10 minutes. Ethyl bromoacetate (1.51 ml) was added to the mixture, and then the resultant was stirred at room temperature for 4 hours, 0.1N hydrochloric acid (200 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgS04) and concentrated. The residue was subjected to silica gel chromatography to obtain an oil from and ethyl acetate-hexane (1:5, v/v)-eluted fraction. This was dissolved in toluene (150 ml), and trifluoroacetic acid (2.64 ml) was added, and then the reaction mixture was stirred at 90° C. for 6 hours. An aqueous saturated solution of sodium bicarbonate was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl 4-(2-furyl)-4-oxobutyrate (2.22 g, yield 79%) as a colorless oil from an ethyl acetate-hexane (1:3, v/v)-eluted fraction.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:13]3[N:14]=[N:15][C:16]([C:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=4)=[CH:17][CH:18]=3)=[C:10]([OH:12])[CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1>CO.[Pd]>[NH:22]1[CH2:21][CH2:20][CH:19]([C:16]2[N:15]=[N:14][C:13]([C:9]3[CH:8]=[CH:7][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:11][C:10]=3[OH:12])=[CH:18][CH:17]=2)[CH2:24][CH2:23]1
Reactant: Oc1cc(-n2cccn2)ccc1-c1ccc(C2=CCNCC2)nn1
Agent: [Pd]
Solvent: CO
Product: Oc1cc(-n2cccn2)ccc1-c1ccc(C2CCNCC2)nn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.5 %

Procedure:
To a round-bottomed flask containing 10% Pd/C (27.7 mg, 0.026 mmol), was added 5-pyrazol-1-yl-2-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyridazin-3-yl]-phenol (Example 19-1) (166 mg, 0.52 mmol) in MeOH (2.5 mL). H2 was bubbled through the solution for 5 min, then the reaction was stirred under H2 at 55 psi at RT. After 18 hr, the reaction mixture was filtered through celite and washed with MeOH. The solvent was removed in vacuo and the resulting oil was dissolved in MeOH then adsorbed onto a MeOH conditioned SCX column. The column was washed several times (5-7 column volume) with MeOH then eluted with 2 N NH3 in MeOH to provide the desired product, 2-(6-(piperidin-4-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol (19.8 mg, 0.06 mmol, 11% yield). LCMS Rt=0.48 min, M+1=322.6 (LCMS method Q). 1H NMR (DMSO-d6) δ 8.63 (d, J=2.5 Hz, 1H), 8.50 (d, J=9.3 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H), 7.76-7.92 (m, 2H), 7.47-7.56 (m, 2H), 6.59 (dd, J=2.5, 1.8 Hz, 1H), 3.24 (s, 2H), 3.07-3.19 (m, 1H), 2.84 (td, J=12.2, 2.4 Hz, 2H), 2.00 (s, 2H), 1.77-1.92 (m, 2H).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([CH3:12])=[CH:8][CH:9]=[CH:10][CH:11]=1)=[NH:5])C.[CH3:13][N:14]([C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH2:15]>C(OCC)C>[CH3:13][N:14]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:5][C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])=[N:15]1
Reactant: CN(N)C(=O)c1ccccc1
Reactant: CCOC(=N)c1ccccc1C
Solvent: CCOCC
Product: Cc1ccccc1-c1nc(-c2ccccc2)n(C)n1
Reaction time: 5 h
Yield: 32 %

Procedure:
A mixture of 1.14 g. of o-toluimidic acid ethyl ester, 1.14 g. of 1-methyl-1-benzoylhydrazine and 0.1 g. of o-toluimidic acid ester hydrochloride, as a catalyst, is heated at about 100° C. for three hours under reduced pressure (about 200 mm Hg) and then at about 120° C. for five hours. The raw material is taken up with diethyl ether and the organic solution is washed with aqueous sodium bicarbonate and then dried over Na2SO4. After evaporation of the solvent, the product is distilled at 170° C./0.1 mm Hg. Yield 32%.
Reaction SMILES: C(C1C=C(C=CC=1)OCC(O)=O)=O.CN1CCCCC1.[CH:21]([C:23]1[CH:24]=[C:25]([CH:43]=[CH:44][CH:45]=1)[O:26][CH2:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36](OC(C)(C)C)=O)[CH2:32][CH2:31]1)=[O:29])=[O:22]>>[CH3:36][N:33]1[CH2:34][CH2:35][N:30]([C:28](=[O:29])[CH2:27][O:26][C:25]2[CH:24]=[C:23]([CH:45]=[CH:44][CH:43]=2)[CH:21]=[O:22])[CH2:31][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)COc2cccc(C=O)c2)CC1
Agent: O=Cc1cccc(OCC(=O)O)c1
Solvent: CN1CCCCC1
Product: CN1CCN(C(=O)COc2cccc(C=O)c2)CC1
Yield: 57 %

Procedure:
2-(3-Formylphenoxy)acetic acid (48) was treated with 1-methylpiperidine in an analogous manner to Compound 49 to afford the desired product (57%) as a colorless oil. LCMS: 99.0% (M++1).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:5]=2[N:4]=[CH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:46][C:47]1[CH:48]=[C:49]([NH:54][C:55](=[O:67])[C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([C:65]#[N:66])([CH3:64])[CH3:63])[CH:57]=2)[CH:50]=[CH:51][C:52]=1[CH3:53]>CN(C=O)C>[C:65]([C:62]([C:58]1[CH:57]=[C:56]([CH:61]=[CH:60][CH:59]=1)[C:55]([NH:54][C:49]1[CH:50]=[CH:51][C:52]([CH3:53])=[C:47]([NH:46][C:11]([C:9]2[S:10][C:5]3[N:4]=[CH:3][C:2](=[O:1])[NH:7][C:6]=3[CH:8]=2)=[O:13])[CH:48]=1)=[O:67])([CH3:64])[CH3:63])#[N:66]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Reactant: O=C(O)c1cc2[nH]c(=O)cnc2s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2[nH]c(=O)cnc2s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 0.3 %

Procedure:
A solution of 2-oxo-1,2-dihydrothieno[3,2-b]pyrazine-6-carboxylic acid 84 (27 mg, 0.138 mmol), TBTU (48.6 mg, 0.151 mmol) and DIPEA (0.068 mL, 0.413 mmol) in DMF (1 mL) was stirred for 15 min. N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide hydrochloride 6 (45.4 mg, 0.138 mmol) in DMF (1 mL) was added and stirred overnight at 50° C. Quenched with water and extracted with EtOAc. Organic layer was washed with water, dried and evaporated. Purification by HPLC gave the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-2-oxo-1,2-dihydrothieno[2,3-b]pyrazine-6-carboxamide 85 (0.2 mg, 0.308%). (m/z)=472 (M+H)+.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[CH:10]=[C:11]([C@H:15]([S:28][CH2:29][C:30]2([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:32][CH2:31]2)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([OH:27])([CH3:26])[CH3:25])[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[OH:7][CH2:8][C:9]1[CH:10]=[C:11]([C@H:15]([S:28][CH2:29][C:30]2([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:32][CH2:31]2)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([OH:27])([CH3:26])[CH3:25])[CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(COC3CCCCO3)c2)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: c1ccncc1
Product: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(CO)c2)CC1
Temperature: 55 °C
Reaction time: 3.5 h
Yield: 0.1 %

Procedure:
To the hydroxy ester from Step 14 (9.02 g, 17.1 mol) in anhydrous MeOH (60 mL) under nitrogen was added pyridine (50 μL) followed by PPTS (1.1 g, 4.3 mmol). The reaction mixture was stirred 3.5 hours at 55° C., then at r.t. overnight before concentrating in vacuo. The residue was diluted with EtOAc (500 mL) and washed with H2O, saturated aq. NaHCO3, NaH2PO4 buffer (pH=4.5) and with brine. After drying over MgSO4 and evaporation of the solvents, the residue was purified by flash chromatography (40% to 60% EtOAc in hexanes) giving 6.85 g (91%) of the title compound. 1H NMR (CD3COCD3): δ5 7.41 (2H, m), 7.27 (3H, m), 7.09 (3H, m), 4.63 (2H, d), 4.19 (1H, t), 3.95 (1H, t), 3.88 (1H, s), 3.57 (3H, s), 3.1 (1H, ddd), 2.8 (1H, ddd), 2.5 (2H, s), 2.4 (2H, d), 2.17 (2H, m), 1.52 (6H, s), 0.52-0.35 (4H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C@@H:13]([C:15]([OH:17])=[O:16])[C@H:12]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>C1(C)C=CC=CC=1.CO>[Cl:25][C:20]1[CH:19]=[C:18]([C@@H:12]2[O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][C@H:13]2[C:15]([O:17][CH3:26])=[O:16])[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C(=O)O)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a mixed solution of (6R,7R)-4-(tert-butoxycarbonyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-6-carboxylic acid (0.82 g) in toluene (10 ml) and methanol (2 mL) was added trimethylsilyldiazomethane (1.576 mL, 2 mol/l hexane solution) at 0° C. and the mixture was stirred for 30 min. Acetic acid was added until the solution became colorless. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.51 g).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][N:16]=[CH:15][C:14]=3[C:18](OCC)=[O:19])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][N:16]=[CH:15][C:14]=3[CH2:18][OH:19])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cnoc1-c1ccc(-c2ccccc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnoc1-c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To a solution of ethyl 5-(4-phenylphenyl)isoxazole-4-carboxylate (10.68 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 83.7 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 5-(4-phenylphenyl)-4-isoxazolylmethanol (7.55 g, yield 83%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 108–110° C.
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[S:19][C:20]([C:33]4[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=4[F:41])=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[N:22]=3)[CH:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[S:19][C:20]([C:33]4[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=4[F:41])=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=4)[N:22]=3)[CH:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: COC(=O)CC(c1cccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)c(-c3cc(OC)ccc3F)s2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2sc(COc3cccc(C(CC(=O)O)C4CC4)c3)nc2-c2ccc(C(F)(F)F)cc2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-(3-((5-(2-fluoro-5-methoxyphenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)methoxy)phenyl)propanoate (120 mg) in THF (3.0 mL) and methanol (3.0 mL) was added 1N aqueous sodium hydroxide solution (3.0 mL), and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid was added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (100 mg) as pale-yellow crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:18][CH2:17]2)=[O:15])=[CH:5]1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[Cl:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6]([C:14]([N:16]3[CH2:17][CH2:18][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[CH2:20][CH2:21]3)=[O:15])=[CH:5][N:4]2[CH2:3][CH2:2][NH:1][C:29](=[O:31])[CH3:30])=[CH:8][CH:9]=1
Reactant: NCCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
[1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone, was treated with acetylchloride (1.05 eq) and triethylamine (1.05 eq) in CH2Cl2 under argon at RT for 2 h to give after purification by prep. HPLC the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([O:13][CH3:14])[C:10]([OH:12])=O.[NH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>>[C:16]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:10](=[O:12])[CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[O:13][CH3:14])=[CH:19][CH:18]=1)#[N:15]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1cccc(F)c1F
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1cccc(F)c1F

Procedure:
(RS)-(2,3-Difluoro-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-(2,3-difluoro-phenyl)-2-methoxy-acetamide. Off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)[S:14](=[O:40])(=[O:39])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15]([CH2:31][C:32]([OH:34])=[O:33])([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:20][CH:19]=2)[S:14](=[O:39])(=[O:40])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC1(c2ccc(Oc3ccccc3)cc2)CCN(C(=O)OCc2ccccc2)CCS1(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1(c2ccc(Oc3ccccc3)cc2)CCN(C(=O)OCc2ccccc2)CCS1(=O)=O
Reaction time: 2 h
Yield: 91.2 %

Procedure:
tert-Butyl 2-[4-benzyloxycarbonyl-7-(4-phenoxyphenyl)perhydro-1,1-dioxo-1,4-thiazepin-7-yl]acetate (56 mg) was dissolved in trifluoroacetic acid (6 ml) at room temperature. After being stirred at the same temperature for 2 hours, the reaction mixture was concentrated in vacuo to give 2-[4-benzyloxycarbonyl-7-(4-phenoxyphenyl)perhydro-1,1-dioxo-1,4-thiazepin-7-yl]acetic acid (46 mg) as a powder.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][C:22]([F:27])=[CH:23][C:24]=3[F:26])[N:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.Cl.NC1CCN(CCN2C3C(=C(F)C=C(F)C=3)N=CC2=O)CC1>O1CCOCC1>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][C:22]([F:27])=[CH:23][C:24]=3[F:26])[N:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3cc(F)cc(F)c32)CC1
Agent: Cl
Agent: NC1CCN(CCn2c(=O)cnc3c(F)cc(F)cc32)CC1
Solvent: C1COCCO1
Product: NC1CCN(CCn2c(=O)cnc3cc(F)cc(F)c32)CC1

Procedure:
tert-Butyl{1-[2-(6,8-difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 194) was deprotected with HCl in dioxane as described for Intermediate 192.