Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(C(C)C)CC)(C)C.[Cl:24][C:25]1[CH:33]=[C:32]([C:34]#[N:35])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>ClCCl>[Cl:24][C:25]1[CH:33]=[C:32]([CH:31]=[CH:30][C:26]=1[C:27]([N:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH2:10][N:4]2[CH:3]=[CH:2][CH:1]=[C:5]2[CH2:6]1)=[O:28])[C:34]#[N:35]
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: N#Cc1ccc(C(=O)Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Reaction time: 1 h

Procedure:
To a stirred suspension of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (7.32 g) and diisopropylethylamine (13.6 ml) in dichloromethane (35 ml) was added under nitrogen the cloudy solution of 2-chloro-4-cyanobenzoyl chloride. After one hour at room temperature, the mixture was diluted with dichloromethane and washed sequentially with water, 5% sodium bicarbonate, and 50% saturated brine, After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to afford a crude product (18.0 g). Purification by column chromatography on silica gel (250 g), eluting with 20% ethyl acetate/hexane, followed by 25% ethyl acetate/hexane, yielded the title compound (13.56 g) as a straw yellow foam, MS (EI), m/z: 347 (M)+.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH3:8][S:7][C:1]1[CH:6]=[CH:5][C:4]([C:20](=[O:21])[CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CSc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1ccc(C(=O)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
Thioanisole (6.22 g, 50 mmol) I) diliuted with CH2Cl2 (5 ml) is added to a suspension of AlCl3. (6.8 g, 51 mmol) in 45 ml of CH2Cl2. Phenylacetyl chloride (7.73 g, 50.0 mmol) in CH2Cl2 (15 ml) is added dropwise at 0° C. over 5 min. Then, the reaction solution is gradually warmed up to room temperature and stirred overnight. The reaction solution is poured onto ice. The resulting white precipitate is extracted with CH2Cl2, and the organic layer is washed with water and NaHCO3 aq. solution, followed by drying over anhydrous MgSO4. After evaporating the solvent, the residue is purified by recrystallization from hexane-CH2Cl2. 10.4 g of a white solid are obtained (86%). 1H NMR (CDCl3), δ[ppm]: d 2.50 (s, 3H), 4.23 (s, 2H), 7.22-7.27 (m, 5H), 7.32 (t, 2H), 7.91 (d, 2H)
Reaction SMILES: [N:1]([CH2:4][C@H:5]([OH:37])[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]([C:19]3([C:22]4[CH:32]=[CH:31][C:25]5[O:26][C:27]([F:30])([F:29])[O:28][C:24]=5[CH:23]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:33]([CH3:36])([CH3:35])[CH3:34])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C@H:5]([OH:37])[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]([C:19]3([C:22]4[CH:32]=[CH:31][C:25]5[O:26][C:27]([F:30])([F:29])[O:28][C:24]=5[CH:23]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:33]([CH3:35])([CH3:34])[CH3:36]
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2n1C[C@@H](O)CN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2n1C[C@@H](O)CN
Reaction time: 18 h
Yield: 70.5 %

Procedure:
To a stirred solution (R)—N-(1-(3-azido-2-hydroxypropyl)-2-tert-butyl-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (2.4 g, 4.0 mmol) in MeOH (25 mL) was added 5% Pd/C (2.4 g) under a Hydrogen gas filled balloon. After 18 h, the reaction mixture was filtered through celite and rinsed with 300 mL ethyl acetate. The organic layer was washed with 1 N HCl and evaporated to give (S)—N-(1-(3-amino-2-hydroxypropyl)-2-tert-butyl-1H-indol-5-yl)-1-(2,2-difluoro-benzo[d][1,3]-dioxol-5-yl)cyclopropane-carboxamide (1.37 g). MS (M+1)=486.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([N:26]3[CH2:31][CH2:30][CH:29]([N:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]3)=[N:9]2)=[CH:5][CH:4]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[C:49](=[O:50])[C:48]([C:51](O)=[O:52])=[CH:47][CH:46]=[N:45]2)=[CH:40][CH:39]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:34][N:32]([CH3:33])[CH:29]1[CH2:30][CH2:31][N:26]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:51]([C:48]4[C:49](=[O:50])[N:44]([C:41]5[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=5)[N:45]=[CH:46][CH:47]=4)=[O:52])=[CH:20][C:19]=3[F:25])[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:36][CH:35]=3)[N:9]=2)[CH2:27][CH2:28]1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(N3CCC(N(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2nc(N3CCC(N(C)C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
A 100 mL round-bottomed flask was charged with 1-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylpiperidin-4-amine (35.8 mg, 0.07298 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (25.63 mg, 0.1095 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (69.95 mg, 0.3649 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (49.30 mg, 0.3649 mmol), N-ethyl-N-isopropylpropan-2-amine (47.16 mg, 0.3649 mmol) and DMF (5 mL). The reaction mixture was stirred at room temperature overnight. Then the reaction was partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (33.1 mg, 64.18%). LRMS (APCI pos): m/e 707 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=1B(O)O.[F-].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB(O)c1cc(F)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Product: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3cc(F)ccc3F)ccc2c1
Temperature: 75 °C
Yield: 46.2 %

Procedure:
Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-yl-ethoxy)-benzyl]-naphthalen-2-yl ester (1.0 g, 1.91 mmol) and add 20 mL degassed acetonitrile. To this solution add 2,5-difluorophenyl boronic acid (0.6 g, 3.82 mmol), transdichlorobis(triphenylphosphine) palladium II, (270 mg, 0.38 mmol) and cesium fluoride (2.61 g, 17.2 mmol). Sonicate the mixture briefly and heat to 75° C. After 3 hours add an additional small amount of the acid, the catalyst and the cesium fluoride and heat overnight. In the morning filter the mixture and run through and SCX column eluting with 2N ammonia in methanol. Purify further on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient. Concentrate to give 430 mg (46%) of the title compound: 1H-NMR (CDCl3, 300 MHz) δ7.85 (d, J=9.3 Hz, 1H); 7.73 (d, J=8.7 Hz, 1H); 7.33 (d, J=8.4 Hz, 1H); 7.18 (d, J=2.7 Hz, 1H); 7.11-6.89 (m, 4H); 6.86-6.82 (m, 2H); 6.73-6.69 (m, 2H); 4.34-4.19 (d, H); 4.04-3.99 (t, 2H); 3.93 (s, 3H); 2.72 (t, J=6.3 Hz, 2H); 2.47 (t, J=5.1 Hz, 4H); 1.58 (qui, J=5.4 Hz, 4H); 1.46-1.41 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]#[N:24])[CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:4])=[O:3].[OH:25][NH:26][C:27](=N)[CH2:28][O:29][CH3:30]>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH3:30][O:29][CH2:28][C:27]1[N:24]=[C:23]([N:20]2[CH2:19][CH2:18][CH:17]([C@H:15]3[CH2:16][C@H:14]3[CH2:13][CH2:12][O:11][C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][N:9]=3)[CH2:22][CH2:21]2)[O:25][N:26]=1
Reactant: COCC(=N)NO
Reactant: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C#N)CC2)nc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COCc1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(S(C)(=O)=O)cn3)CC2)n1
Temperature: 25 °C

Procedure:
To a solution of 4-((1R,2S)-2-(2-(5-(methylsulfonyl)pyridin-2-yloxy)ethyl)cyclopropyl)piperidine-1-carbonitrile (Step A, Example 98; 80 mg, 0.23 mmol) and N-hydroxy-2-methoxyacetimidamide (38 mg, 0.37 mmol) in tetrahydrofuran (5 mL) was added zinc chloride (0.6 mL, 0.5 M in tetrahydrofuran, 0.3 mmol). The mixture was refluxed for 2 h, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in 2 mL of 4N HCl ethanol and water (1:1). The solution was refluxed for 30 min, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (5 mL), neutralized by the addition of excess potassium carbonate, mixed silica gel (2 g), and concentrated to dryness under reduced pressure. The residue was loaded on a silica gel column (10 g of silica gel) and eluted with a gradient of dichloromethane/CMA, 19:1, 500 mL; 4:1, 500 mL to provide the title compound as an off-white solid, 1H NMR (300 MHz, CDCl3) δ 8.72 (d, J=2.4 Hz, 1H), 8.03 (dd, J=2.5, 8.7 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H), 4.50 (t, J=7.2 Hz, 2H), 4.38 (s, 2H), 4.25-4.10 (m, 2H), 3.46 (s, 3H), 3.15-2.95 (m, 2H), 3.08 (s, 3H), 2.20-2.05 (m, 1H), 1.95-1.80 (m, 2H), 1.60-1.40 (m, 3H), 1.20-0.85 (m, 2H), 0.80-0.55 (m, 2H), −0.08 (q, J=4.6 Hz, 1H). MS (ESI) m/z 437 [M+H]+. MP: 68-70° C. GPR119 Human EC50: 7 nM
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[C:25]([F:27])[CH:26]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.O[CH:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH:53]([N:57]2[CH:61]=[C:60]([C:62]3[C:63]4[CH:70]=[CH:69][N:68](COCC[Si](C)(C)C)[C:64]=4[N:65]=[CH:66][N:67]=3)[CH:59]=[N:58]2)[CH2:54][C:55]#[N:56])[CH2:48][CH2:47]1.[F:79][C:80]([F:85])([F:84])[C:81]([OH:83])=[O:82].C(N)CN>C1COCC1.C(Cl)Cl.C(#N)C>[F:79][C:80]([F:85])([F:84])[C:81]([OH:83])=[O:82].[F:79][C:80]([F:85])([F:84])[C:81]([OH:83])=[O:82].[F:79][C:80]([F:85])([F:84])[C:81]([OH:83])=[O:82].[F:20][C:21]1[CH:22]=[C:23]([CH:24]=[C:25]([F:27])[CH:26]=1)[O:28][CH:46]1[CH2:47][CH2:48][N:49]([CH2:52][CH:53]([N:57]2[CH:61]=[C:60]([C:62]3[C:63]4[CH:70]=[CH:69][NH:68][C:64]=4[N:65]=[CH:66][N:67]=3)[CH:59]=[N:58]2)[CH2:54][C:55]#[N:56])[CH2:50][CH2:51]1
Reactant: Oc1cc(F)cc(F)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCC(O)CC4)c3)ncnc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: NCCN
Solvent: CC#N
Product: N#CCC(CN1CCC(Oc2cc(F)cc(F)c2)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 0.25 h
Yield: 30 %

Procedure:
To a mixture of resin of triphenylphosphine (54.6 mg, 0.114 mmol) in THF (0.6 mL) was added 3,5-difluorophenol (10.1 mg, 0.0778 mmol) and di-tert-butyl azodicarboxylate (19.1 mg, 0.0830 mmol). The mixture was stirred for 15 minutes before adding 4-(4-hydroxypiperidin-1-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (25.0 mg, 0.0519 mmol). The reaction was stirred overnight at room temperature and the solvent was evaporated. The vial and resin were washed with DCM and filtered. The filtrates were washed with 10% aq. NaOH solution. The organic was collected and concentrated to give the crude product. The crude residue was dissolved in methylene chloride (0.20 mL) and trifluoroacetic acid (0.17 mL) was added. The mixture was stirred for 2 hours then concentrated. The residue was dissolved in methanol (0.5 mL) followed by adding ethylenediamine (0.10 mL, 1.50 mmol). After stirring for 1 hour, the mixture was diluted with acetonitrile and purified by preparative LCMS (C18 column eluting with a gradient of acetonitrile (ACN)/H2O containing 0.1% trifluoroacetic acid (TFA)) to afford the desired product (12.6 mg, 30%). 1H NMR (CD3OD) δ9.08 (s, 1H), 8.92 (s, 1H), 8.60 (s, 1H), 7.86 (s, 1H), 7.27 (s, 1H), 6.64 (d, 2H), 6.54 (t, 1H), 5.56 (m, 1H), 4.70 (s, 1H), 4.21 (t, 2H), 3.74 (d, 1H), 3.52 (br, 2H), 3.28 (m, 4H), 2.15 (m, 4H). LCMS (M+H)+: 464.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[CH3:14].C([O-])=O.[NH4+]>C1COCC1.CO.[Pd]>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[CH3:14]
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(N)cc1C
Reaction time: 3 h

Procedure:
To a solution of 2-methyl-4-nitro phenylacetic acid methyl ester (10 mmol) in dry THF (20 mL) and methyl alcohol (20 mL), ammonium formate (0.1 mol) and 10% Pd/C (0.5 g) have been added and the resulting mixture has been left stirring for 3 h, until complete disappearance of the starting reagent. The catalyst has been filtered off and the filtrate evaporated under vacuum to give 2-methyl-4-amino phenylacetic acid methyl ester as a waxy solid (9.22 mmol).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.C1([O:35][C:36](=O)[NH:37][C:38]2[N:39]([C:47]3[CH:52]=[CH:51][N:50]=[C:49]([N:53]([CH2:55][CH2:56][N:57]([CH3:59])[CH3:58])[CH3:54])[N:48]=3)[N:40]=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:42]=2)C=CC=CC=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:43]([C:41]1[CH:42]=[C:38]([NH:37][C:36]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:35])[N:39]([C:47]2[CH:52]=[CH:51][N:50]=[C:49]([N:53]([CH2:55][CH2:56][N:57]([CH3:58])[CH3:59])[CH3:54])[N:48]=2)[N:40]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CN(C)CCN(C)c1nccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccnc(N(C)CCN(C)C)n4)c4ccccc43)cn12
Temperature: 70 °C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
A solution of Intermediate 81d (25 mg, 0.066 mmol) in 1,4-dioxane (0.7 mL) was treated with Intermediate 140c (32 mg, 0.073 mmol) and DIPEA (0.014 mL, 0.083 mmol) and the mixture was stirred at 70° C. for 18 h. The cooled solution was concentrated in vacuo, and the residue was partitioned between DCM and water. The phases were separated and the aqueous layer was extracted with DCM (×2). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to a brown gum. FCC, using 0-8% MeOH in DCM, gave a colourless glass (27 mg). The glass was purified further by HPLC (Phenomenex Gemini C18 column, 5-95% MeCN in H2O, 0.1% HCO2H) over 30 mins. Concentration of the fractions in vacuo gave a colourless glass that was dissolved in ether. A solid was precipitated out of solution by addition of cyclohexane. The solid was filtered off to give the title compound as a white solid (8 mg, 17%). LCMS (Method 5): Rt 4.07 min, m/z 721.6 [MH+]. 1H NMR (400 MHz, d6-DMSO, 353K): 0.92 (3H, d, J=6.4 Hz), 1.29 (9H, s), 1.49-1.58 (2H, m), 1.65-1.72 (2H, m), 1.77-1.86 (2H, m), 1.99 (6H, s), 2.00-2.14 (4H, m), 2.20-2.29 (1H, m), 3.12-3.19 (5H, m), 3.30-3.39 (1H, m), 3.58-3.72 (2H, m), 4.94-5.02 (1H, m), 5.42 (1H, t, J=3.9 Hz), 6.55 (1H, s), 7.03 (1H, d, J=5.5 Hz), 7.15 (1H, dd, J=9.8, 2.3 Hz), 7.22-7.27 (1H, m), 7.31-7.37 (2H, m), 7.41-7.45 (1H, m), 7.56-7.61 (2H, m), 7.70 (1H, br s), 8.35 (1H, d, J=5.5 Hz), 10.18 (1H, br s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:27])[C:16](=[O:26])[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=2)=[CH:4][CH:3]=1.[CH:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.O>CCOC(C)=O.C(=O)([O-])O.[Na+]>[CH:28]1([C:34]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:27])[C:16](=[O:26])[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH:9]=3)=[CH:4][CH:3]=2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CN(Cc1cccc(-c2ccc(N)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CN(Cc1cccc(-c2ccc(NC(=O)C3CCCCC3)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 99.8 %

Procedure:
tert-Butyl (2-{[(4′-aminobiphenyl-3-yl)methyl](methyl)amino]-2-oxoethyl}carbamate (240 mg) was dissolved in a mixed solution of EtOAc (10 ml)/saturated aqueous sodium hydrogen carbonate solution (10 ml), followed by ice-cooling. A solution of cyclohexanecarbonyl chloride (142 mg) in EtOAc (5 ml) was added dropwise thereto. The reaction mixture was returned to room temperature and stirred for 24 hours, and then to the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane=2/1) to obtain tert-butyl {2-[({4′-[(cyclohexylcarbonyl)amino]biphenyl-3-yl}methyl)(methyl)amino]-2-oxoethyl}carbamate (311 mg).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>O1CCCC1>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)CSc1ccc(O)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 4-mercaptophenol (49.7 mg, 0.39 mmol) in tetrahydrofuran (2 mL) was added cesium carbonate (128 mg, 0.39 mmol) and ethyl bromoaceate (44 μL, 0.39 mmol) and the reaction was stirred at 50° C. overnight. The reaction was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with hexanes and EtOAc to afford ethyl 2-(4-hydroxyphenylthio)acetate (507).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[CH2:33]([CH2:35][NH2:36])[OH:34]>CS(C)=O>[OH:34][CH2:33][CH2:35][NH:36][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccc(Cl)cc4)c3)csc12
Solvent: CS(C)=O
Product: O=C(Nc1cccc(OCc2csc3c(C(=O)NCCO)cncc23)c1)c1ccc(Cl)cc1
Temperature: 135 °C

Procedure:
A suspension of 3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (30 mg, 0.064 mmol) (from Example 4 supra) in methyl sulfoxide (1 mL) and ethanolamine (3 mL) (Aldrich) was heated at 135° C. for 2 hours in a microwave reactor. After cooling to room temperature, the precipitate was filtered off, washed with MeOH and dried to give 3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)amide as a white solid. (Yield 13.2 mg, 42.6%).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.C(=O)([O-])[O-].[Ca+2].[O:41]=[C:42]([CH:46]=[CH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:43]([O-:45])=[O:44].[K+].S(=O)(=O)(O)O>O>[OH:41][C@H:42]([CH:46]=[CH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:43]([OH:45])=[O:44]
Reactant: O=C([O-])C(=O)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)[C@H](O)C=Cc1ccccc1
Temperature: 30 °C
Reaction time: 48 h

Procedure:
A medium comprising 2% of glucose, 1% of yeast extract, 1% of peptone, 10 ppm of MnSO4 and 1% of calcium carbonate was used for lactic acid bacteria; a medium comprising 1% of glucose, 0.5% of yeast extract, 0.5% of peptone, 0.5% of meat extract and 0.5% of NaCl (pH 7) was used for other bacteria; and a medium comprising 2% of glucose, 0.3% of yeast extract, 0.5% of peptone and 0.3% of malt extract (pH 6) was used for yeasts. 100 ml of each medium was introduced into a 500-ml Erlenmeyer flask and sterilized. Then one platinum loopful, of each strain listed in Table 1 was inoculated into the corresponding medium and subjected to rotary shaking culture for 48 hours. After the completion of the culture, the cells were separated by centrifuging and washed with a physiological saline solution once to thereby yield viable cells. 50 ml of distilled water was introduced into a 500-ml Erlenmeyer flask and the above-mentioned viable cells were suspended therein. After adding 5 g of sucrose and 0.5 g of calcium carbonate thereto, the mixture was shaken at 30° C. for 10 minutes. Then 0.5 g of potassium 2-keto-4-phenyl-3-butenoate was added thereto and the mixture was allowed to react under shaking at 30° C. for 40 hours. After the completion of the reaction, the pH value of the reaction mixture was adjusted to 1 or below with sulfuric acid. It was then extracted with 100 ml of ethyl acetate, and the solvent was removed from the extract. Then the amount and optical purity of the (R)-2-hydroxy-4-phenyl-3-butenoic acid thus formed were determined by high-performance liquid chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15](=[O:21])[CH:16](Cl)[C:17]([CH3:19])=O)[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[O:8][C:7]([C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:9][C:17]=1[CH3:19])=[O:21])[CH3:13]
Reactant: COc1ccc(C(N)=O)cc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1oc(-c2ccc(OC)cc2)nc1C
Temperature: 50 °C

Procedure:
40.0 g 4-Methoxybenzamide was dissolved in 400 ml ethanol. The mixture was warmed to 50° C. and 48.8 ml ethyl-2-chloroacetoacetate was added in one portion. The resulting mixture was refluxed for four days. The reaction mixture was cooled and the solvent removed under reduced pressure. The resulting residue was purified by flash chromatography on silica gel to obtain 23.5 g 2-(4-Methoxy-phenyl)-4-methyl-oxazole-5-carboxylic acid ethyl ester as a solid.