Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:16]=[C:17]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:18]([NH2:21])=[CH:19][CH:20]=3)=[N:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(O)(=O)C.[N:36]([O-])=O.[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]4[N:21]=[N:36][N:22]([C:23]5[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=5)[C:17]=4[CH:16]=3)=[N:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: COc1ccc(Nc2cc(-c3nnc(CCc4cccc(F)c4)o3)ccc2N)cc1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(-n2nnc3ccc(-c4nnc(CCc5cccc(F)c5)o4)cc32)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
To a mixture of 4-[5-[2-(3-fluorophenyl)ethyl]-1,3,4-oxadiazol-2-yl]-N2-(4-methoxyphenyl)benzene-1,2-diamine (0.20 g, 0.49 mmol), 6 M hydrochloric acid (2.5 mL) and acetic acid (2.5 mL) was added an aqueous solution (0.25 mL) of sodium nitrite (41 mg, 0.59 mmol) at 0° C., and the obtained mixture was stirred at 0° C. for 30 min and at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=1/1) and recrystallized from hexane/ethyl acetate to give the title compound (51.2 mg, yield 25%) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[OH-].[Na+].CO.Cl>O.O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(=O)OCC)CC2)c2ncnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(=O)O)CC2)c2ncnn12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanoate (13 g), 2 N aqueous sodium hydroxide solution (50 mL), methanol (50 mL) and tetrahydrofuran (50 mL) was stirred at 50° C. for 3 hr. Water (20 mL) and 1 N hydrochloric acid were added to the reaction mixture, and the mixture was adjusted to pH 4, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (11 g, 93%).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](O)=[O:28].[CH3:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]2([NH2:44])[CH2:43][CH2:42]2)[N:36]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:30]=[C:26]([C:27](=[O:28])[NH:44][C:41]2([C:37]3[N:36]=[C:35]([CH3:34])[CH:40]=[CH:39][N:38]=3)[CH2:43][CH2:42]2)[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[CH3:33]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Reactant: Cc1ccnc(C2(N)CC2)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nccc(C)n5)CC4)c(OC)cc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.089 mmol, 1 eq), 1-(4-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.06 g, 0.11 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.027 g, 0.26 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.022 g (42%). 1H NMR (400 MHz, CD3OD): δ 8.54 (d, J=5.6 Hz, 1H), 7.97-7.94 (m, 2H), 7.90 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 4H), 7.19 (s, 1H), 4.10 (s, 3H), 2.96 (s, 3H), 2.55 (s, 3H), 2.31 (s, 3H), 1.89-1.86 (m, 2H), 1.59-1.56 (m, 2H). 19F NMR (376.57 MHz, CD3OD): δ−77.65 (TFA), −112.33, −122.77 LCMS: (ES+) m/z=583.2 (M+H)+
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:17]([O:21][C:22](=[O:41])[NH:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:34]1[CH:39]=[C:38](Cl)[N:37]=[CH:36][N:35]=1)([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([O:21][C:22](=[O:41])[NH:23][C:24]1[CH:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[CH:26][C:25]=1[C:34]1[CH:39]=[C:38]([O:1][C:2]2[C:7]3[N:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[S:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)[N:37]=[CH:36][N:35]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)ccc1-c1cc(Cl)ncn1
Reactant: CC(=O)Nc1nc2c(O)cccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)OC(C)(C)C)ncn3)cccc2s1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of N-(4-hydroxybenzo-thiazol-2-yl)-acetamide, (Example 144(c)), (96 g, 27 mmol) in DMF (200 mL) was added NaH (0.68 g, 28 mmol, 60% dispersion in oil, Aldrich) and the mixture was stirred at 0° C. for 15 min. [2-(6-Chloro-pyrimidin-4-yl)-5-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester, (Example 148(b)), (10 g, 26 mmol) was then added and the reaction mixture was allowed to warm to room temperature, and stirred for 4.5 h. The reaction mixture was quenched with H2O (200 mL) and poured into a solution containing 30% ethyl acetate/hexanes (500 mL) and 1 N NaOH (800 mL). A white precipitate which formed was filtered and the filtercake was washed with H2O (100 mL) and 10% EtOAc/hexanes (100 mL). The filtercake was dried in vacuum, redissolved in an acetone/methanol mixture and adsorbed on silica gel. Purification by silica gel chromatography (2:1 EtOAc/hexanes) afforded the product as a white crystalline solid. Mp: 194–195° C. MS (ESI, pos. ion) m/z: 546 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:27][CH:28]=[CH2:29])[C:10]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][O:25][CH3:26])=[CH:19][CH:18]=3)([CH3:16])[C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[OH:12][C:13]1[CH:14]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:6]=[CH:7][C:8]=1[CH:9]([CH2:27][CH:28]=[CH2:29])[C:10]([C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][O:25][CH3:26])=[CH:21][CH:22]=1)([CH3:16])[CH2:11][OH:15]
Reactant: C=CCC1c2ccc(OCOC)cc2OC(=O)C1(C)c1ccc(OCOC)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCC(c1ccc(OCOC)cc1O)C(C)(CO)c1ccc(OCOC)cc1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 99.4 %

Procedure:
A solution of (3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methyl-4-(2-propenyl)chroman-2-one (6.91 g) in anhydrous tetrahydrofuran (26 ml) was added dropwise to an ice-cold suspension of lithium aluminum hydride (1.65 g) in anhydrous tetrahydrofuran (50 ml) over 20 minutes under nitrogen atmosphere, and the reaction mixture was then stirred on ice for 50 minutes. Ethyl acetate (20 ml) and saturated aqueous ammonium chloride (20 ml) were added to stop the reaction, followed by stirring for 1 hour at room temperature. The reaction mixture was filtered through cellite and the resulting filtrate was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous ammonium chloride, dried over magnesium sulfate and then concentrated under reduced pressure to give (2RS,3RS)-3-(2-hydroxy-4-methoxymethoxyphenyl)-2-(4-methoxymethoxyphenyl)-2-methyl-5-hexen-1-ol (6.94 g, Yield 99.4%) as a crude product, which was then used for the subsequent reaction without further purification.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26]>>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Nc1ccccc1O
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1O
Yield: 58.5 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 278 mg of 2-aminophenol in place of the 2,4-difluoroaniline. 370 mg of N-(2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][CH:11]3[CH2:20][N:14]4[CH2:15][CH2:16][NH:17][C:18](=[O:19])[CH:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1>CN(C)C=O>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:20][N:14]4[CH2:15][CH2:16][N:17]([CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=5)[C:18](=[O:19])[C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: O=C1NCCN2CC(Oc3cnc(C4CC4)cn3)CC12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1[C@@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN2CCN1Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26.9 %

Procedure:
To a solution of 7-(5-cyclopropylpyrazin-2-yloxy)hexahydro-pyrrolo[1,2-a]pyrazin-1(2H)-one (50 mg, 0.182 mmol) from Step 3 [3:1 (7R,8aS: 7R,8aR) diastereomer ratio] in N,N-dimethylformamide (0.7 mL) under nitrogen was added sodium hydride (60% weight suspension in mineral oil; 8.75 mg, 0.219 mmol), and the resulting suspension was stirred at room temperature. After 20 minutes, the suspension was treated with 1-(bromomethyl)-3-(trifluoromethyl)benzene (0.033 mL, 0.219 mmol) with stirring continued for 4 hours at room temperature. The reaction mixture was partitioned between water (3 mL) and ethyl acetate (3×2 mL), and the organic phase was dried over sodium sulfate. The solvent was concentrated under a stream of nitrogen, and the crude material was purified by flash chromatography on a 12 g silica gel cartridge eluted with a gradient 0-5% methanol/dichloromethane over 17 minutes to give the crude product as an oil. The crude oil (40 mg) was loaded onto a 2×0.25 mm silica gel prep plate and eluted with ethyl acetate to give the title compound (21 mg, 0.049 mmol, 26.6% yield) as the first of 2 diastereomers to elute as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.07 (d, J=1.0 Hz, 1H), 7.94 (d, J=1.1 Hz, 1H), 7.55 (dd, J=4.4, 3.4 Hz, 1H), 7.48 (t, J=9.0 Hz, 3H), 5.44 (dd, J=6.9, 5.7 Hz, 1H), 4.73 (d, J=14.8 Hz, 1H), 4.58 (d, J=14.8 Hz, 1H), 3.71 (t, J=8.0 Hz, 1H), 3.46 (dt, J=12.2, 7.1 Hz, 1H), 3.38 (dd, J=10.9, 5.7 Hz, 1H), 3.20 (dt, J=12.1, 3.9 Hz, 1H), 3.02 (dd, J=6.7, 3.8 Hz, 2H), 2.88 (dd, J=10.8, 2.9 Hz, 1H), 2.53 (dt, J=15.2, 7.6 Hz, 1H), 2.44 (dd, J=14.5, 7.8 Hz, 1H), 2.03-1.95 (m, 1H), 1.00-0.88 (m, 4H); MS (ESI+) m/z 433 (M+H)+.
Reaction SMILES: [CH3:1]C(C)=O.C(=O)([O-])[O-].[K+].[K+].CI.[OH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[OH:24])[O:20][C:19]([CH3:26])([CH3:25])[CH2:18][C:17]2=[O:27]>>[OH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:1])[O:20][C:19]([CH3:25])([CH3:26])[CH2:18][C:17]2=[O:27]
Reactant: CC1(C)CC(=O)c2cc(O)c(O)cc2O1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COc1cc2c(cc1O)C(=O)CC(C)(C)O2
Temperature: 5 °C
Yield: 90 %

Procedure:
In 100 ml of acetone 4.2 g (20 millimoles) of 6,7-dihydroxy-2,2-dimethyl-4-chromanone are dissolved and to the solution thus obtained 4.1 g (30 millimoles) of potassium carbonate and 4.5 g (2 ml, 30 millimole) of methyl iodide are added under stirring. The reaction mixture is refluxed for 4 hours. The inorganic salt is filtered off, washed twice with 20 ml of acetone each and the solvent is removed. The residue is suspended in 100 ml of chloroform and extracted twice with 50 ml of a 4% sodium hydroxide solution each. The aqueous-alkaline phase is separated, cooled to 5° C. and acidified with 37% hydrochloric acid under constant stirring. The precipitated product is filtered off, washed twice with 20 ml of water each and dried to constant weight. The product is purified by recrystallization from anhydrous ethanol. Thus 4.0 g of the desired compound are obtained, yield 90%. Mp.: 134°-136° C.
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.N.N#N.S(=O)(=O)(O)O.[NH2:17][C@H:18]([C:23]([O-:25])=[O:24])[CH2:19][C:20]([O-:22])=[O:21].[NH4+].[NH4+]>O>[NH2:17][C@H:18]([C:23]([OH:25])=[O:24])[CH2:19][C:20]([OH:22])=[O:21]
Reactant: N[C@@H](CC(=O)[O-])C(=O)[O-]
Agent: N
Agent: N#N
Agent: O=C(O)/C=C\C(=O)O
Solvent: O
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
A reaction solution containing maleic acid (116 g) and ammonia (153 ml) (having a total volume of 1,000 ml by adding water), which had been previously subjected to N2 substitution by carrying out agitation while blowing N2 gas in it for 30 minutes, was transferred into a jar fermenter having a volume of 3 L. The recovered microbial cells of the both species (IFO 12669 strain: 20 g, AB-41 strain: 120 g) were added thereto, followed by agitation while supplying N2 at a velocity of 0.02 vvm to carry out a reaction at 30° C. for 36 hours with sealing. After completion of the reaction, a supernatant was recovered by centrifugation. The obtained supernatant of the reaction solution was subjected to thin layer chromatography (developing solvent: n-butanol: acetic acid: water=4:1:1 (volume ratio), coloring agent: ninhydrin reagent). As a result, it was confirmed that 128 g/L of L-aspartic acid was produced. Sulfuric acid was added to this ammonium aspartate solution to adjust pH to 3. Thus aspartic acid was precipitated, washed with water, and then dried to obtain crystals of aspartic acid. The obtained crystals had an amount of 125 g.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].Cl.Cl.[NH2:22][C:23]1[C:38]([Cl:39])=[CH:37][C:26]([C:27]([NH:29][CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:28])=[C:25]([O:40][CH3:41])[CH:24]=1.O>CN(C)C=O>[NH2:22][C:23]1[C:38]([Cl:39])=[CH:37][C:26]([C:27]([NH:29][CH2:30][CH:31]2[CH2:32][CH2:33][N:34]([CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:35][CH2:36]2)=[O:28])=[C:25]([O:40][CH3:41])[CH:24]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCBr)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCC(=O)c2ccccc2)CC1
Reaction time: 7.5 h
Yield: 52.6 %

Procedure:
Potassium carbonate (0.57 g) and 5-bromo-1-phenyl-1-pentanone (0.80 g) were added to a solution (45 ml) of 4-amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) in dimethylformamide, and the mixture was stirred at 70°-80° C. for 7.5 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give crystals. The obtained crystals were recrystallized from ethyl acetate to give 0.80 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-oxo-5-phenylpentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C:14]([C:15]([O:17]C)=O)=[CH:13][CH2:12][N:11]1[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:26][Cl:27].C([Li])CCC.CCCCCC.P([O-])([O-])([O-])=O>C1COCC1.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C@@H:10]1[C:14]([C:15](=[O:17])[CH2:26][Cl:27])=[CH:13][CH2:12][N:11]1[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)N1CC=C(C(=O)OC)[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: ClCBr
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCOC(=O)N1CC=C(C(=O)CCl)[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a solution of 1-allyl 3-methyl (2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (0.20 g, 0.55 mmol) and bromochloromethane (54 ml, 0.83 mmol) in THF (6 ml) was added at −90 to −80° C. a solution of n-butyllithium in hexane (1.59M, 0.52 ml, 0.83 mmol) over a 10 minutes period. After stirring for additional 30 minutes, the reaction mixture was poured into a mixture of ice (10 g) and phosphate buffer (pH 7.0, 10 ml). After ethyl acetate was added and the mixture was separated with a separating funnel, the aqueous layer was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride, dried over magnesium sulfate and the organic solvent was removed under reduced pressure. The residue was purified by silica gel (27 g) chromatography to give allyl (2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(chloroacetyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (163 mg, 79%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[C:14](OC(=O)C)(=[O:16])[CH3:15].Cl>>[C:14]([O:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:16])[CH3:15]
Reactant: Cc1c(O)cccc1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1cccc(C(=O)O)c1C
Temperature: 5 °C
Yield: 90 %

Procedure:
60.9 g (0.40 mol) of 3-hydroxy-2-methylbenzoic acid are introduced into 500 ml of 2N sodium hydroxide solution (1.00 mol) with stirring and the solution formed in the course of this is cooled to 5° C. 61.3 g (0.60 mol) of acetic anhydride are added to the cooled solution. The reaction mixture is cooled here such that the temperature does not exceed 8° C. The reaction mixture is then acidified with 88 ml of 37% hydrochloric acid. The precipitated product is filtered off, washed three times with 50 ml of water and dried in vacuo. 69.9 g of 3-acetoxy-2-methylbenzoic acid are obtained. This corresponds to a yield of 90.0% of theory.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH2:24][OH:25])[CH2:4][CH3:5])[CH3:2].C=O.[CH3:28]C1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([CH:3]([N:6]1[C:7]2[C:8](=[C:9]([NH:14][C:15]3[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=3[CH3:21])[N:10]=[C:11]([CH3:13])[CH:12]=2)[CH2:24][O:25][CH2:28]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: Cc1ccccc1
Product: CCC(CC)N1COCc2c1cc(C)nc2Nc1c(C)cc(C)cc1C
Yield: 193.2 %

Procedure:
A mixture of [4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanol(280 mg, 0.82 mmol), 37% aqueous formaldehyde(0.35 ml) and p-TsOH (78 mg, 0.41 mmol) in 10 ml of toluene was heated at reflux using a Dean-Stark apparatus for 3 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give 280 mg of a green oil. The oil was purified through silica gel column chromatography using EtOAc as eluent to give the title compound as a brown oil. 1H NMR (CDCl3) δ 6.89 (s,2H), 6.09(s,IH), 4.51(s,2H), 4.19(s,2H), 3.53(m,1H), 2.25(s,6H), 2.15(s,6H), 1.55(m,4H), 0.90(t,6H)ppm.
Reaction SMILES: [CH3:1][CH:2]1[N:8]2[C:9]3[N:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:10]=3[CH:11]=[C:7]2[C:6](=[O:19])[NH:5][CH2:4][CH2:3]1.ClC(N(C)C)=C(C)C.[CH2:28]([C:35]1[O:39][N:38]=[C:37]([NH2:40])[CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:28]([C:35]1[O:39][N:38]=[C:37]([NH:40][C:16]([C:14]2[CH:13]=[CH:12][C:10]3[CH:11]=[C:7]4[C:6](=[O:19])[NH:5][CH2:4][CH2:3][CH:2]([CH3:1])[N:8]4[C:9]=3[N:15]=2)=[O:18])[CH:36]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Nc1cc(Cc2ccccc2)on1
Reactant: CC1CCNC(=O)c2cc3ccc(C(=O)O)nc3n21
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1CCNC(=O)c2cc3ccc(C(=O)Nc4cc(Cc5ccccc5)on4)nc3n21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
To a suspension of 10-methyl-6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxylic acid (Intermediate G, 75 mg, 0.29 mmol) in CH2Cl2 (5 mL) is added 1-chloro-N,N,2-trimethylpropenylamine (138 μL, 1.01 mmol) and the mixture is stirred at room temperature for 30 min. 5-benzyl-1,2-oxazol-3-amine (Intermediate W, 252 mg, 1.45 mmol) and pyridine (94 μL, 1.16 mmol) are added and the reaction is stirred at room temperature for 20 h. The mixture is concentrated under reduced pressure and the residue is purified via preparative HPLC using a gradient elution from 10-90% acetonitrile/H2O with 0.1% TFA to afford the title compound (19 mg, 16%). LCMS: 416.20 (M+H+). (System V-med polar)
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@@H:24]5[CH2:28][C@@H:27]([F:29])[CH2:26][NH:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH3:37][O:38][CH2:39][CH2:40]Br>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@@H:24]5[CH2:28][C@@H:27]([F:29])[CH2:26][N:25]5[CH2:40][CH2:39][O:38][CH3:37])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: COCCBr
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1C[C@@H](F)CN1
Product: COCCN1C[C@H](F)C[C@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S,4R)-4-fluoro-1-(2-methoxyethyl)pyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S,4R)-4-fluoropyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione (Example 184) and 2-bromoethyl methyl ether following General Procedure S.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.O.[CH3:19]O>>[OH:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:19])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)/C=C/c1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)/C=C/c1cccc(O)c1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
To a solution of (E)-3-(3-hydroxyphenyl)acrylic acid (15.0 g) in methanol (100 mL) was added sulfuric acid (2.0 mL), and the mixture was stirred at 70° C. for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (15.8 g) as white crystals. This compound was used for the next step without further purification.