Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].Br[CH2:14][C:15]#[N:16].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC#N>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[C:6]([NH:7][CH2:14][C:15]#[N:16])[CH:8]=[CH:9][CH:10]=1
Reactant: N#CCBr
Reactant: Nc1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: N#CCNc1cccc(OC(F)(F)F)c1
Yield: 74.2 %

Procedure:
A mixture of 3-(trifluoromethoxy)aniline (1.00 g, 5.64 mmol), bromoacetonitrile (745 mg, 6.21 mmol), sodium iodide (1.86 g, 12.4 mmol), and sodium carbonate (858 mg, 6.21 mmol) in CH3CN (15 mL) was heated at reflux for 18 h, then partitioned between water and EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane/EtOAc gradient) afforded the title compound (904 mg, 74%). Brown liquid, MS: 215.2 (M+H)+.
Reaction SMILES: [C:1]1([CH:7](O)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCOCC>C1(C)C=CC=CC=1>[CH3:9][CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC=Cc1ccccc1
Temperature: 75 °C
Yield: 94 %

Procedure:
A mixture of 1-phenyl-1-propanol (0.16 g, 1.17 mmol) and Catalyst A or B (30 mg) in toluene (1 ml) was stirred and heated at 75° C. for 10 h under nitrogen. Ether (20 ml) was added and the mixture was filtered to remove the catalyst. The organic washings were concentrated under reduced pressure at room temperature to afford β-methyl styrene as a colourless oil (0.13 g, 92%).
Reaction SMILES: [CH2:1]([Si]1(Cl)N(C)[C@@H](C)[C@H](C2C=CC=CC=2)O1)[CH:2]=[CH2:3].[CH:18](=[N:25][NH:26][C:27](=[O:29])[CH3:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CO>C(Cl)Cl>[C:19]1([C@H:18]([NH:25][NH:26][C:27](=[O:29])[CH3:28])[CH2:3][CH:2]=[CH2:1])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)NN=Cc1ccccc1
Reactant: C=CC[Si]1(Cl)O[C@@H](c2ccccc2)[C@H](C)N1C
Solvent: CO
Solvent: ClCCl
Product: C=CC[C@@H](NNC(C)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.7 %

Procedure:
Enantioselective allylation of acetic acid benzylidene-hydrazide (8) to give (1R)-acetic acid N′-(1-phenyl-but-3-enyl)-hydrazide: To a cooled (10° C.) solution of (4S,5S)-2-Allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine (9.90 g, 37.0 mmol) in CH2Cl2 (300 mL) was added acetic acid benzylidene-hydrazide (5.00 g, 30.8 mol) as a solid. The resulting solution was stirred for 16 hours and methanol (40 mL) was then added. After 15 min all volatiles were removed by distillation and the residue was diluted with EtOAc (150 mL) and H2O (500 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2×150 mL). The combined organic layers were washed with H20 and brine, dried (MgSO4), filtered and concentrated. Analysis of the residue by HPLC revealed an ee of 87%. The residue was dissolved in boiling toluene (80 mL) and the solution was then cooled to ambient temperature. Pentane (380 mL) was layered on top of the toluene solution and the resulting biphasic solution was allowed to stand for 16 hours. The resulting crystalline solid precipitate was filtered, washed (pentane:toluene (5:1)) and then dried in vacuo to give 5.04 g (80%) of (1R)-acetic acid N′-(1-phenyl-but-3-enyl)-hydrazide in 98% ee.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:33](=[O:34])[CH:32]=[N:31][C:30]5[CH:35]=[CH:36][C:37]([F:39])=[N:38][C:29]4=5)[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:40].C(OCC)(=O)C>CO>[ClH:40].[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:33](=[O:34])[CH:32]=[N:31][C:30]5[CH:35]=[CH:36][C:37]([F:39])=[N:38][C:29]4=5)[CH2:22][CH2:21]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)cnc3ccc(F)nc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=c1cnc2ccc(F)nc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 90 mg of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(6-fluoro-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamate in 1 mL of methanol, 1 mL of a 4 mol/L hydrogen chloride/ethyl acetate solution was added, and the mixture was stirred at room temperature for 1 hour. The solid was filtered off to obtain 76 mg of 4-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-6-fluoropyrido(2,3-b)pyrazin-3(4H)-one hydrochloride.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[C:25]([O:26][CH3:27])=[C:24]([Cl:28])[C:23]([F:29])=[CH:22][C:9]=1[C:10]([C:12](=[CH:17][NH:18][CH:19]1[CH2:21][CH2:20]1)[C:13]([O:15][CH3:16])=[O:14])=[O:11]>CN(C=O)C>[CH:19]1([N:18]2[C:8]3[C:9](=[CH:22][C:23]([F:29])=[C:24]([Cl:28])[C:25]=3[O:26][CH3:27])[C:10](=[O:11])[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17]2)[CH2:21][CH2:20]1
Reactant: COC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)c(OC)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C2CC2)c2c(OC)c(Cl)c(F)cc2c1=O
Temperature: 42.5 °C
Reaction time: 2.5 h
Yield: 90.3 %

Procedure:
34.7 g of anhydrous K2CO3 (0.35 mol) was added to a solution of 62.6 g of methyl 2-(2,4-dichloro-5-fluoro-3-methoxybenzoyl)-3-cyclopropylaminoacrylate in 220 ml of DMF. The reactant was stirred at 40-45° C. for 2.5 hours, and the reaction was monitored by TLC. The resulting mixture was then poured into 800 ml of ice-water, filtered, washed with water (100 ml×2), and dried. The resulting solid was dissolved in 120 ml of 95% methanol and then refluxed for 15 minutes, cooled, filtered and dried to afford 50.8 g of methyl 1-cyclopropyl-7-chloro-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylate (0.156 mol) as a white solid, mp 184-187C., in 90.1% yield.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[C:5]([CH3:19])[NH:4][N:3]=1.Cl.[CH3:21]O>>[CH3:21][O:17][C:16]([C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([C:6]3[C:2]([NH2:1])=[N:3][NH:4][C:5]=3[CH3:19])[S:8][C:9]=2[CH:15]=1)=[O:18]
Reactant: Cc1[nH]nc(N)c1-c1nc2ccc(C(=O)O)cc2s1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc2nc(-c3c(N)n[nH]c3C)sc2c1

Procedure:
A solution of 2-(3-amino-5-methyl-1H-pyrazol-4-yl)-benzothiazole-6-carboxylic acid (1.52 g, 5.5 mmol) in 500 mL of anhydrous methanol containing HCl gas was heated to reflux for 5 hrs. The excess methanol was removed by distillation and the solution was neutralized by the addition of a solution of saturated sodium carbonate. The resulting solids were isolated by filtration to yield 500 mg of the title compound as a yellow solid. MS (m/z, ES+): 289.1 (M+1,100%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH:9]=O)[CH2:4][CH2:3]1.Cl.[CH2:12]([O:14][C:15]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24]N)=[CH:20][CH:19]=1)=[O:16])C.C(=O)(O)[O-].[Na+]>CO.O>[C:15]([CH2:17][C:18]1[CH:23]=[C:22]2[C:21](=[CH:20][CH:19]=1)[NH:24][CH:9]=[C:8]2[CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)([O:14][CH3:12])=[O:16]
Reactant: CN1CCC(CC=O)CC1
Reactant: CCOC(=O)Cc1ccc(NN)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)Cc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Temperature: 25 °C
Yield: 39.3 %

Procedure:
A solution of 1-methyl-4 (formylmethyl)piperidine (2.3 g, 16 mmol) and 4-(ethoxycarbonylmethyl)phenyl hydrazine hydrochloride (3.7 g, 16 mmol) in methanol:water (20:1) (25 ml) was stirred at room temperature for 1 hour. Polyphosphoric acid (7 g) was then added and the mixture heated at reflux for 5 hours, under nitrogen. The mixture was then cooled to ambient temperature, basified with saturated sodium bicarbonate to pH9, and extracted with dichloromethane (2×20 ml). The organic phases were combined, dried (MgSO4) and evaporated to give a brown residue. This was chromatographed (eluant 50:8:1 dichloromethane:ethanol:ammonia) to give 4-[5-carbomethoxymethyl-1H-indol-3-yl]N-methylpiperidine (1.8 g, 39%) as a yellow solid. mp 105°-107° C. δ(360 MHz, CDCl3) δ1.85 (2H, m), 2.16 (4H, m), 2.36 (3H, s), 2.81 (1H, m), 3.00 (2H, m), 3.70 (3H, s), 3.73 (2H, s), 6.97 (1H, d, J=2 Hz), 7.10 (1H, dd, J=8 and Hz), 7.31 (1H, d, J=8 Hz), 7.53 (1H, s), 7.97 (1H, brs).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[C@H:15]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[C@@H:16]([OH:27])[C@@H:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O[CH2:39][C:40]([CH3:46])=[CH:41]C(C)(C)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[C@H:15]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=1)[C@@H:16]([O:27][CH2:41][C:40]([CH3:46])=[CH2:39])[C@@H:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=CC(C)(C)C)COC(=O)[O-]
Reactant: Cc1ccc(C[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@@H](O)[C@H](C)OCc2ccccc2)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: C=C(C)CO[C@@H]([C@H](C)OCc1ccccc1)[C@@H](Cc1ccc(C)cc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a 250 mL round bottom flask were added (R)-4-benzyl-3-((2R,3R,4S)-4-(benzyloxy)-3-hydroxy-2-(4-methylbenzyl)pentanoyl)oxazolidin-2-one (11.2 g, 23 mmol) and anhydrous THF (145 mL). The solution was sparged with N2 for 5 min and then tris(dibenzylideneacetone)-dipalladium (0) (Pd2(dba)3; 2.10 g, 2.3 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (dppf; 2.55 g, 4.59 mmol) were added, and the resulting dark solution was sparged with N2 for an additional 5 minutes. The reaction mixture was warmed to 55° C. under N2 and treated with a solution of tert-butyl(2-methylallyl) carbonate (7.9 g, 45.9 mmol) in THF (5 mL). The dark mixture was stirred at 55° C. for 1 h and then cooled to room temperature, The reaction mixture was filtered through paper, rinsing with CH2Cl2, and the filtrate was evaporated to give a dark oil. The oil was partially purified by flash chromatography (SiO2, 0→30% acetone/hexanes) to give (R)-4-benzyl-3-((2R,3R,4S)-4-(benzyloxy)-3-((2-methylallyl)oxy)-2-(4-methylbenzyl)pentanoyl)oxazolidin-2-one (9.36 g) as a yellow oil that is contaminated with dibenzylideneacetone (dba): 1H NMR (400 MHz, CDCl3) δ 7.22 (m, 10H), 7.02 (d, J=7.8 Hz, 2H), 6.87 (m, 2H), 5.06 (m, 1H), 4.91 (s, 1H), 4.77 (ddd, J=11.7, 9.3, 4.7 Hz, 1H), 4.64 (d, J=11.9 Hz, 1H), 4.31 (d, J=11.9 Hz, 1H), 4.16 (s, 2H), 3.96 (m, 1H), 3.74 (dd, J=9.2, 7.1 Hz, 1H), 3.62 (p, J=6.1 Hz, 1H), 3.41 (m, 2H), 2.85 (m, 2H), 2.70 (dd, J=13.7, 3.5 Hz, 1H), 2.26 (s, 3H), 2.17 (s, 3H), 1.49 (dd, J=13.7, 10.6 Hz, 1H), 1.34 (d, J=6.1 Hz, 3H); ESIMS m/z 565 ([M+Na]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=[O:11].[C:13]1([CH2:19][C:20]([NH2:22])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:19]1([C@H:9]2[C@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=3)[C:10](=[O:11])[NH:12][C:10]2=[O:11])[C:13]2=[C:18]3[C:17](=[CH:16][CH:15]=[CH:14]2)[CH2:7][CH2:2][CH2:3][N:22]3[CH:20]=1
Reactant: NC(=O)Cc1ccccc1
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccccc1

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-phenyl-pyrrolidine-2,5-dione was prepared according to the Example 40 replacing 2-chloro-4-fluorophenylacetamide with phenylacetamide. 1H NMR (DMSO-d6) 400 MHz δ: 11.511 (s, 1H), 7.24-7.36 (m, 6H), 7.13 (d, 1H, J=7.2), 6.8-6.88 (m, 2H), 4.49 (d, 1H, J=8.0 Hz), 4.3 (d, 1H, J=7.6 Hz), 4.08 (m, 2H), 2.88 (m, 2H), 2.088 (m, 2H).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:15]([N:22]([CH2:34][C@H:35](O)[CH3:36])[C:23]1[C:28]([NH:29][C:30](=[O:32])[CH3:31])=[CH:27][CH:26]=[C:25]([Br:33])[N:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:15]([N:22]1[CH2:34][C@H:35]([CH3:36])[N:29]([C:30](=[O:32])[CH3:31])[C:28]2[CH:27]=[CH:26][C:25]([Br:33])=[N:24][C:23]1=2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)Nc1ccc(Br)nc1N(Cc1ccccc1)C[C@@H](C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(Br)nc2N(Cc2ccccc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
Diisopropyl azodicarboxylate (0.763 mL, 3.93 mmol) was slowly added to a solution of (R)-N-(2-(benzyl(2-hydroxypropyl)amino)-6-bromopyridin-3-yl)acetamide (1.35 g, 3.57 mmol) and triphenylphosphine (1.030 g, 3.93 mmol) in THF (35.7 mL). A mild exotherm was observed. The reaction mixture stirred at room temperature for 30 minutes and was then concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 10:1 dichloromethane-ethyl acetate) to afford (S)-1-(4-benzyl-6-bromo-2-methyl-3,4-dihydropyrido[2,3-b]pyrazine-1 (2H)-yl)ethanone (0.93 g, 72%). MS (ESI, pos. ion) m/z 360, 362 [M+1]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.COC(C1C=NC(OCC2C(C3C=CC(Cl)=CC=3)=NOC=2)=CN=1)=O>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(-c2ccncn2)noc1C
Agent: COC(=O)c1cnc(OCc2conc2-c2ccc(Cl)cc2)cn1
Product: Cc1onc(-c2ccncn2)c1C(=O)O
Yield: 74.5 %

Procedure:
As described for example 112a, 5-methyl-3-pyrimidin-4-yl-isoxazole-4-carboxylic acid ethyl ester (500 mg, 2.1 mmol) was converted, instead of 5-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid methyl ester, to the title compound (321 mg, 73%) which was obtained as an off white solid. MS: m/e=204.1 [M−H]−.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[OH-].[Na+].[Cl:16][C:17]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:19]([C:20]([O-])=[O:21])[C:18]=1[OH:27].Cl>O1CCOCC1>[Cl:16][C:17]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:19]([C:20]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:21])[C:18]=1[OH:27]
Reactant: NCCCCCCCCCC(=O)O
Reactant: O=C([O-])c1cc(Cl)cc(Cl)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCCCCCCCCNC(=O)c1cc(Cl)cc(Cl)c1O
Temperature: 90 °C

Procedure:
A slurry of 3.0 g of (16.0 mmol, 1.1 eq) 10-aminodecanoic acid, 9 ml (18.0 mmol, 1.13 eq) of 2 N aqueous sodium hydroxide and 30 ml of dioxane was added to a white slurry of 3.97 g (20.8 mmol, 1.3 eq) of oligo (3,5-dichlorosalicylate) and 30 ml of dioxane in a 250 mL round bottom flask equipped with a magnetic stir bar and reflux condenser. The reaction mixture was heated to 90° C. for 20 hours (at which time no further change was observed, by HPLC). The reaction mixture was cooled to 25° C. and acidified to pH=1 with 2N aqueous hydrochloric acid. The mixture was concentrated in vacuo (60° C., 50 mm). The resulting solid was recrystallized twice from ethanol-water decolorized with charcoal but was not yet clean. Column chromatography using 5:1 hexanes/ethyl acetate-1% acetic acid as eluant gave one fraction as acid and another as ethyl ester. The ethyl ester was hydrolyzed to the acid using 4 ml of 2N aqueous sodium hydroxide and acidified with 2N aqueous hydrochloric acid. The acid was isolated by filtration. The combined acid portions were triturated with methylene chloride and hexanes to give 1.22 g of N-(3,5-dichlorosalicyloyl)-10-aminodecanoic acid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:33])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][C:21]=2[CH3:32])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].O.C(O)(=O)C>O1CCCC1.CO>[CH2:3]([NH:10][C:11](=[O:33])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][C:21]=2[CH3:32])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
200 mg (5.0 mmol, 4.2 eq) of sodium hydroxide are added to a solution of 360 mg (0.85 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-methylbiphenyl-4-yl]propanoate in 6 ml of a tetrahydrofuran/methanol mixture (8/2). The reaction mixture is stirred at room temperature for 3 hours. The reaction medium is hydrolyzed with water, acidified with acetic acid solution and extracted with ethyl acetate. The organic phases are combined, washed with sodium chloride solution and dried over sodium sulfate. The solvent is evaporated off and the residual oil is chromatographed on silica (7/3 to 1/1 heptane/ethyl acetate). 185 mg of 3-[3′-(3-heptyl-1-methylureido)-2-methylbiphenyl-4-yl]propanoic acid are obtained in oil form. Yield=53%
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:20](=[O:21])[C:19]3[S:18][C:17]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[C:11]=3[CH:10]=[N:9]2)[C:3]=1[CH:22]=[O:23].[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:50]=[C:44]3[CH2:45][N:46]([CH3:49])[CH2:47][CH2:48][N:43]3[N:42]=2)[C:26]1=[O:51].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O.O.C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH3:24][N:25]1[C:26](=[O:51])[C:27]([NH:40][C:41]2[CH:50]=[C:44]3[CH2:45][N:46]([CH3:49])[CH2:47][CH2:48][N:43]3[N:42]=2)=[CH:28][C:29]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[C:20](=[O:21])[C:19]4[S:18][C:17]5[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=5[C:11]=4[CH:10]=[N:9]3)[C:3]=2[CH:22]=[O:23])=[CH:30]1
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Reactant: CN1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6c7c(sc6c5=O)CCCC7)c4C=O)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 87.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a reflux condenser was charged with 4-chloro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl}pyridine-3-carbaldehyde 124a (210 mg, 0.60 mmol), 1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-5-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 135a (346 mg, 0.90 mmol), Pd(dppf)Cl2 (30 mg, 0.030 mmol), K3PO4 (270 mg, 1.2 mmol), sodium acetate trihydrate (180 mg, 1.2 mmol), water (6 drops), and acetonitrile (40 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 181a (300 mg, 88%) as a yellow brown solid. MS-ESI: [M+H]+ 569.3.
Reaction SMILES: O.[OH:2][C:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:14])(=[O:13])[N:5]([CH3:15])[C:4]=1[C:16]1[NH:20][N:19]=[N:18][N:17]=1.[OH:21][C:22]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2S(=O)(=O)N(C)C=1C1NN=NN=1.C(Cl)(=O)C1C=CC=CC=1.Cl>N1C=CC=CC=1>[C:22]([O:2][C:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:13])(=[O:14])[N:5]([CH3:15])[C:4]=1[C:16]1[NH:20][N:19]=[N:18][N:17]=1)(=[O:21])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:26]=1
Reactant: CN1C(c2nnn[nH]2)=C(O)c2ccccc2S1(=O)=O
Agent: Cl
Solvent: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CN1C(c2nnn[nH]2)=C(OC(=O)c2ccccc2)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-hydroxy-2-methyl-3-(tetrazol-5-yl)-1,2-benzothiazine 1,1-dioxide hemihydrate (2.88 g) in pyridine (10 ml) was added dropwise benzoyl chloride (1.02 ml) at 5°-10° C. After being stirred at room temperature for 1 hour, the mixture was poured into 0.6N HCl (200 ml) with vigorous stirring. The resulting solids were collected by filtration and washed with water. The solids were dissolved in dichloromethane (100 ml), washed with water and dried over sodium sulfate to give crude 4-benzoyloxy-2-methyl-3-(tetrazol-5-yl)-1,2-benzothiazine 1,1-dioxide, 4.24 g.
Reaction SMILES: C(O)C.B([O-])([O-])O[C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[S:27](=[O:29])(=[O:28])[CH2:26][CH2:25][C:24]([C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][N:40]([CH3:47])[CH:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[CH:35][CH:34]=3)=[O:31])=[CH:23][C:22]=2[CH:48]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[S:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=[C:6]1[C:18]1[CH:19]=[CH:20][C:21]2[S:27](=[O:29])(=[O:28])[CH2:26][CH2:25][C:24]([C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][N:40]([CH3:47])[CH:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[CH:35][CH:34]=3)=[O:31])=[CH:23][C:22]=2[CH:48]=1
Reactant: [O-]B([O-])Oc1cc2ccccc2s1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4cc5ccccc5s4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reaction time: 0.5 h
Yield: 8.2 %

Procedure:
In toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) were suspended benzothiophen-2-yl borate (134 mg), 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) and potassium carbonate (208 mg), and the suspension was stirred under argon atmosphere for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (47 mg), and the mixture was stirred, under argon atmosphere, at 100° C. for 1 day and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate (twice). The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography and recrystallized from ethanol to give colorless crystals of 7-(benzothiophen-2-yl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 145) (27 mg).
Reaction SMILES: C([OH:3])C.C([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](P(=O)(O)O)=[O:20])=[CH:14][CH:13]=1)C1C=CC=CC=1.Cl.NO.O.O.O.C([O-])(=O)C.[Na+]>O>[OH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([OH:20])=[O:3])=[CH:16][CH:17]=1
Reactant: CCO
Reactant: O=C(Cc1ccc(OCc2ccccc2)cc1)P(=O)(O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: O
Product: O=C(O)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At first, 1,200 ml of ethanol and 400 ml of water were added to 428 g (1.18 moles) of the compound (d) in a nitrogen atmosphere to prepare a homogeneous solution. Then, 101 g (1.45 moles) of hydroxylamine hydrochloride and 373 g (2.74 moles) of sodium acetate trihydrate were added thereto, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to about 1,000 ml, and extracted with ethyl ether (3×300 ml). The ethyl ether layer was washed successively with an aqueous 5% sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution (each 2×100 ml), and dried over anhydrous sodium sulfate. The solvent was removed therefrom under reduced pressure to obtain 441 g of the compound (a) as an orange oily substance (99.1%).