Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:4]=1[CH:5]=[O:6].[OH-:16].[K+].OO.Cl>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:7][C:4]=1[C:5]([OH:16])=[O:6]
Reactant: [OH-]
Reactant: COc1ccc(OC(F)(F)F)cc1C=O
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CO
Product: COc1ccc(OC(F)(F)F)cc1C(=O)O
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To a stirred solution of 2-methoxy-5-trifluoromethoxybenzaldehyde (2.0 g, 9.09 mmol) and 50% KOH (4.1 ml) in MeOH (15 ml) at 65° C. was added dropwise hydrogen peroxide (30%, 7.4 ml) over 20 min. The reaction mixture was then stirred at 65° C. for 10 min., cooled to room temperature, acidified with 1 M HCl, and extracted with Et2O (3×40 ml). The combined organic extracts were washed with brine (35 ml), dried (Na2SO4) and the solvent removed under reduced pressure to give a pale yellow viscous oil which solidified at room temperature overnight to give the title compound (1.95 g, 91%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:3]=12.[O-:17][C:18]#[N:19].[K+]>O>[C:18]([N:14]1[CH2:15][CH2:16][C:3]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH2:12][CH2:13]1)(=[O:17])[NH2:19]
Reactant: Cc1c2c(nc3ccccc13)CCNCC2
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Product: Cc1c2c(nc3ccccc13)CCN(C(N)=O)CC2
Reaction time: 5 h

Procedure:
3.3 gm (11.6 millimols) of 1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline were reacted with 0.04 gm (11.6 millimols) of potassium cyanate at room temperature in 50 ml of water. After 4 to 6 hours, the reaction product crystallized out. Yield: 1 gm (34% of theory); m.p. 215° C (decomp.).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[N:3]1.[CH2:10]([N:14]1[C:22]2[N:21]=[C:20]([Cl:23])[NH:19][C:18]=2[C:17](=[O:24])[N:16]([CH2:25][CH2:26][CH2:27][CH2:28]/[C:29](=[N:32]/[H])/[NH:30]O)[C:15]1=[O:34])[CH2:11][CH2:12][CH3:13]>CN(C=O)C.CS(C)=O>[CH2:10]([N:14]1[C:22]2[N:21]=[C:20]([Cl:23])[NH:19][C:18]=2[C:17](=[O:24])[N:16]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[N:30]=[C:7]([C:5]3[N:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[O:9][N:32]=2)[C:15]1=[O:34])[CH2:11][CH2:12][CH3:13]
Reactant: Cn1cc(C(=O)O)nn1
Reactant: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O)NO
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CCCCn1c(=O)n(CCCCc2noc(-c3cn(C)nn3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 100 °C
Yield: 28.7 %

Procedure:
A solution of the 1-methyl-1H-1,2,3-triazole-4-carboxylic acid (18 mg, 0.14 mmol) in DMF (0.5 ml) was treated with CDl (23 mg, 0.14 mmol) at rt for 1 h. A solution of (1Z)-5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (50 mg, 0.14 mmol) in DMSO (0.4 ml) was added to the mixture then heated to 100° C. for 18 h. The reaction mixture was purified by MDAP to give the title compound as a white solid (18 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([Sn](C)(C)C)=[N:14][N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:10]3=[CH:11][N:12]=2)[CH:2]=1.Br[C:29]1[N:34]=[C:33]([F:35])[C:32]([Cl:36])=[CH:31][CH:30]=1.O1CCCC1.[F-].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.[Pd](Cl)Cl.[Cu]I>[Cl:36][C:32]1[CH:31]=[CH:30][C:29]([C:15]2[C:9]3[C:10](=[CH:11][N:12]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)[N:13]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:14]=2)=[N:34][C:33]=1[F:35]
Reactant: Fc1nc(Br)ccc1Cl
Reactant: C[Si](C)(C)CCOCn1nc([Sn](C)(C)C)c2cc(-c3cccnc3)ncc21
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(Cl)c(F)n2)c2cc(-c3cccnc3)ncc21
Temperature: 45 °C

Procedure:
To a solution of 5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethylstannyl)-1H-pyrazolo[3,4-c]pyridine (1.3490 g, 2.7571 mmol) and 6-bromo-3-chloro-2-fluoropyridine (696.23 mg, 3.3086 mmol) in tetrahydrofuran (10 mL, 100 mmol) under Argon in a pressure tube was added Cesium fluoride (837.64 mg, 5.5143 mmol), Palladium(II) Chloride (24.446 mg, 0.13786 mmol), Copper(I) iodide (52.510 mg, 0.27571 mmol), and 1.000 M of Tri-tert-butylphosphine in Toluene (275.71 uL) at room temperature. The tube was sealed and the mixture was heated at 45° C. overnight. The mixture was cooled to room temperature, and filtered through Celite®. The filter cake was washed with ethyl acetate; the combined organic layer was washed with brine, dried with MgSO4, and then concentrated. The residue was purified on silica eluted with 0 to 100% EtOAc in Heptane to afford 3-(5-chloro-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine as a yellow oil, which solidified upon standing.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:15][O:16][C:17](=[O:20])[CH2:18][NH2:19].C(N(CC)CC)C.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH3:15][O:16][C:17](=[O:20])[CH2:18][NH:19][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNC(=O)Cc1cccc([N+](=O)[O-])c1
Yield: 90.1 %

Procedure:
To a stirred solution of 3-nitrophenylacetic acid (10 g, 0.055 mol), glycine methyl ester hydrochloride (7.3 g, 0,058 mol), triethylamine (8.0 ml, 0.058 mol) and 4-dimethylaminopyridine (7.1 g, 0,058 mol) in dichloromethane (200 ml) was added, under nitrogen, 1-(3-dimethylaminopropyl )-3-ethylcarbodiimide(11.1 g, 0.058 mol), the mixture was stirred at room temperature for 18 h then the solvent removed in vacuo. Ethyl acetate (300 ml) was added to the residue and the mixture partitioned with 1M hydrochloric acid (2×200 ml), saturated sodium bicarbonate solution (2×200 ml), water (100 ml) and brine (100 ml). The organic phase was separated then evaporated in vacuo. The residue was triturated with ether (200 ml) to afford the desired amide (12.5 g, 90%) as a white solid. mp 104°-105° C. 1H NMR (360MHz, CDCl3) δ3.71 (2H, s), 3.76 (3H, s), 4.06 (2H, d, J 5Hz), 6.06 (1H, br s), 7.53 (1H, dd, J=8 and 8Hz), 7.67 (1H, d, J =8Hz), 8.16 (2H, m).
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH:17]([NH2:19])[CH3:18])=[N:9][C:10]3[C:15]([CH:16]=2)=[N:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:21]12[N:29]=[CH:28][N:27]=[C:26]1[C:25](Cl)=[N:24][CH:23]=[N:22]2.CCN(C(C)C)C(C)C>CCCCO>[C:1]1([C:7]2[C:8]([CH:17]([NH:19][C:25]3[N:24]=[CH:23][N:22]=[C:21]4[C:26]=3[N:27]=[CH:28][NH:29]4)[CH3:18])=[N:9][C:10]3[C:15]([CH:16]=2)=[N:14][CH:13]=[CH:12][CH:11]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(N)c1nc2cccnc2cc1-c1ccccc1
Reactant: NC12N=CN=C(Cl)C1=NC=N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2cccnc2cc1-c1ccccc1
Temperature: 25 °C
Yield: 81 %

Procedure:
1-(3-Phenyl-1,5-naphthyridin-2-yl)ethanamine (46 mg, 0.19 mmol), 4-amino-6-chloropurine (28.5 mg, 1.0 eq) and hunig's base (39 μL, 1.2 eq) in n-BuOH (2 mL) was heated to 130° C. overnight. The mixture was cooled to rt, concentrated, and purified by reverse phase HPLC (MeCN/H2O/0.1% TFA, 10% to 60%) to give a white powder (50 mg) as TFA salt. 1H NMR (400 MHz, CD3OD) δ ppm 9.05 (1H, d, J=4.0 Hz), 8.65 (1H, d, J=8.0 Hz), 8.50-8.47 (2H, m), 8.29 (1H, s), 7.90 (1H, dd, J=8.0, 4.0 Hz), 7.62-7.47 (5H, m), 6.12-6.01 (1H, m), 1.63 (3H, d, J=8.0 Hz); LC-MS (ESI) m/z 368 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]O)[CH:21]=1.C(C=P(CCCC)(CCCC)CCCC)#N.CCCCCC>C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: OCc1cccnc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(Cc1cccnc1)c1cc(F)ccc1F
Yield: 57.8 %

Procedure:
Under an argon atmosphere, the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (120 mg, 0.396 mmol) obtained in Example 5 and 3-pyridylmethanol (50.1 μl, 0.515 mmol) were dissolved in toluene (4 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (124 mg, 0.515 mmol). The resulting mixture was heated under reflux for 18 hours under an argon atmosphere. The reaction mixture was then concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=3:7 eluate was concentrated. The solid thus obtained was recrystallized from ethyl acetate-hexane, whereby the title compound (90.3 mg, 0.229 mmol, 58%) was obtained as colorless columnar crystals.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[NH2:54][C@@H:55]1[C:86](=[O:87])[N:57]2[C:58]([C:70]([O:72][CH:73]([C:80]3[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=3)[C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)=[O:71])=[C:59]([CH2:62][S:63][C:64]3[CH2:68][O:67][C:66](=[O:69])[CH:65]=3)[CH2:60][S:61][C@H:56]12>CN(C)C=O.N1C=CC=CC=1>[O:69]=[C:66]1[CH:65]=[C:64]([S:63][CH2:62][C:59]2[CH2:60][S:61][C@@H:56]3[C@H:55]([NH:54][C:27](=[O:28])/[C:26](/[C:24]4[N:25]=[C:21]([NH:20][C:1]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[S:22][CH:23]=4)=[N:30]\[O:31][CH2:32][C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[C:86](=[O:87])[N:57]3[C:58]=2[C:70]([O:72][CH:73]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)=[O:71])[CH2:68][O:67]1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSC3=CC(=O)OC3)CS[C@H]12
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSC3=CC(=O)OC3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
A stirred solution of 2-(2-tritylaminothiazol-4-yl)-2-(Z)-(t-butyloxycarbonyl)methoxyiminoacetic acid (498 mg) in dimethylformamide (4 ml) was cooled to -55° C. to -60° C. and N,N-diisopropylethylamine (0.157 ml) was added, followed by methanesulphonyl chloride (0.068 ml). The mixture was stirred at the same temperature for 0.5 h and then diphenylmethyl 7β-amino-3-(2,5-dihydro-2-oxofuran-4-ylthiomethyl)ceph-3-em-4-carboxylate (395 mg) and pyridine (0.064 ml) were added. The mixture was then stirred at 0° for 1.25 h, and then partitioned between ethyl acetate and citric acid solution. The organic phase was washed successively with water, sodium bicarbonate solution, water and brine. The solution was dried over magnesium sulphate and evaporated. The product (567 mg) was isolated by column chromatography of the residue using gradient elution (Kieselgel 1:1 going to 3:7 hexane: ethyl acetate as eluent). υmax (CHCl3) 3400, 3250, 1790, 1745, 1730 and 1680cm-1 ; δ(CDCl3) 1.43 (9H, s), 3.40 (1H, d, J 18.0Hz), 3.56 (1H, d, J 18.0Hz), 3.91 (1H, d, J 12.4Hz), 4.02 (1H, d, J 12.4Hz), 4.72 (2H, s), 4.73 (1H, d, J 17.1Hz), 4.81 (1H, d, J 17.1Hz), 5.08 (1H, d, J 4.9Hz), 5.66 (1H, s), 5.93 (1H, dd, J 4.9 and 8.3Hz), 6.82 (1H, s), 6.95 (1H, s,), 7.01 (1H, s), 7.2-7.45 (25H, m), 8.77 (1H, d, J 8.3Hz).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:3]1.Cl.Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][N:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:11][CH:12]=2)[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:3]1
Reactant: Cn1nc(-c2ccncc2)c(-c2ccc(O)cc2)n1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Temperature: 65 °C
Yield: 79.4 %

Procedure:
A mixture of 4-(2-methyl-5-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl)phenol (80 mg, 0.32 mmol), 2-(chloromethyl)quinoline hydrochloride (71 mg, 0.33 mg), and cesium carbonate (414 mg, 1.27 mmol) in dimethylformamide was heated at 65° C. for 20 h, filtered, the filtrate concentrated and chromatographed on silica eluted with ethyl acetate-hexanes providing material containing starting phenol. This was dissolved in ethyl acetate, washed with aqueous NaOH, dried and concentrated giving a colorless solid (100 mg, 80%). 1H NMR (CDCl3, 400 mHz) δ 8.56 (d, 2H, J=6.2 Hz), 8.24 (d, 1H, J=8.3 Hz), 8.12 (d, 1H, J=8.3 Hz), 7.85 (d, 1H, J=8.3 Hz), 7.75 (ddd, 1H, J=8.5, 7, 1.6 Hz), 7.70 (d, 1H, J=8.7 Hz), 7.65 (d, 2H, J=6.2 Hz), 7.57 (m, 1H), 7.41 (m, 2H), 7.08 (m, 2H), 5.45 (s, 2H), 4.27 (s, 3H). MS (AP+) m/e 394 (MH+).
Reaction SMILES: OC(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:22]=1[C:16]1([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[N:15]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:14]2=[S:32].C([O-])([O-])=O.[K+].[K+].[CH:39]12[CH2:48][CH:43]3[CH2:44][CH:45]([CH2:47][CH:41]([CH2:42]3)[CH:40]1[N:49]=[C:50]=[O:51])[CH2:46]2.NC(N)=O>CC#N>[Cl:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:22]=1[C:16]1([CH2:21][CH2:20][N:19]([C:50]([NH:49][CH:40]3[CH:39]4[CH2:48][CH:43]5[CH2:44][CH:45]([CH2:47][CH:41]3[CH2:42]5)[CH2:46]4)=[O:51])[CH2:18][CH2:17]1)[N:15]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[C:14]2=[S:32]
Reactant: COc1ccc(CN2C(=S)c3cccc(Cl)c3C23CCNCC3)cc1
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Agent: NC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2C(=S)c3cccc(Cl)c3C23CCN(C(=O)NC2C4CC5CC(C4)CC2C5)CC3)cc1
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of crude 7-chloro-2-(4-methoxybenzyl)spiro[isoindoline-1,4′-piperidine]-3-thione TFA salt (prepared from TFA deprotection of tert-butyl 7-chloro-2-(4-methoxybenzyl)-3-thioxospiro[isoindoline-1,4′-piperidine]-1′-carboxylate (52 mg, 0.11 mmol)) in 1:1 MeCN:10% aq K2CO3 (10 mL), was added 2-adamantylisocyanate (50 mg, 0.30 mmol, 2.6 equiv) and the mixture stirred was for 2 h. After this time LC-MS analysis showed formation of the desired urea. The mixture was concentrated to ˜50% of its original volume and diluted with EtOAc. The mixture was washed with 1.0 M aq HCl and brine, dried over Na2SO4, and evaporated. The residue was purified by flash chromatography on silica gel (4 g), eluting with 20-80% EtOAc in hexanes, affording 7-chloro-N-(2-adamantyl)-2-(4-methoxybenzyl)-3-thioxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide (51 mg, 0.093 mmol, 85% yield) of the desired thiolactam-urea as a pale yellow solid.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]([NH:24][C@H:25]([C:27]([NH:29][C@H:30]([C:38]([NH:40][C@H:41]([C:46]([OH:48])=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:28])[CH3:26])=[O:23])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=O)(C)(C)C.[ClH:49]>O1CCOCC1>[ClH:49].[NH2:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]([NH:24][C@H:25]([C:27]([NH:29][C@H:30]([C:38]([NH:40][C@H:41]([C:46]([OH:48])=[O:47])[CH2:42][CH:43]([CH3:44])[CH3:45])=[O:39])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:28])[CH3:26])=[O:23])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O

Procedure:
The N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanyl-L-phenylalanyl-L-leucine is dissolved in 100 parts dioxane and stirred with a ten-fold excess of 2 N HCl in dioxane at room temperature for 15 minutes. The solvent is then removed under reduced pressure and the residue triturated with ethyl ether. The resulting solid is precipitated from the mixture of methanol and ether to afford L-tyrosylglycyl-L-alanyl-L-phenylalanyl-L-leucine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([OH:17])=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:17])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: C1COCCN1
Reactant: COc1ccc(C2(C(=O)O)CCOCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: COc1ccc(C2(C(=O)N3CCOCC3)CCOCC2)cc1
Yield: 87 %

Procedure:
The title compound (3.1 g, 87%) was prepared using 4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-carboxylic acid, morpholine and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) similarly to the procedure used for example 166. HRMS ESI+ m/z 306.1696 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14](Cl)=[N:15][OH:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.O1CCCC1.[C:25]([C:27]1[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:26]=[C:25]([C:27]4[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=4)[O:16][N:15]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: ON=C(Cl)Cc1ccc(Oc2ccc(F)cc2)nc1
Reactant: C#Cc1cccnc1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(Oc3ccc(F)cc3)nc2)no1
Temperature: 55 °C
Reaction time: 5 h
Yield: 31.9 %

Procedure:
To a mixture of (6-(4-fluoro-phenoxy)-pyridin-3-yl)-acetohydroximoyl chloride (25 mg) described in Manufacturing Example 75-1-4 and tetrahydrofuran (1 mL) were added 3-ethynyl-pyridin-2-ylamine (6.0 mg, 0.051 mmol) described in Manufacturing Example 1-2-3 and triethylamine (21 μL, 0.15 mmol), which was stirred for 5 hours at 55° C. The reaction mixture was cooled to room temperature and water was added thereto at that temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (5.9 mg, 32%).
Reaction SMILES: [CH2:1]([Li])[CH3:2].C(Br)C.[Li].[CH3:8][O:9][C:10]1[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[OH:21])=[O:13].[Cl-].[NH4+]>O1CCCC1.CCOCC>[CH3:8][O:9][C:10]1[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[OH:21])([OH:13])[CH2:1][CH3:2]
Reactant: COc1ccccc1C(=O)c1ccc(O)cc1O
Reactant: [Li]CC
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CCBr
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(O)cc1O)c1ccccc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ethyl lithium solution prepared from 29.4 g. of ethyl bromide and 3.7 g. of lithium in 33o ml. of dry ether, under argon atmosphere, which is cooled to -10° C., a solution of 11 g. of 2-methoxy-2',4'-dihydroxy-benzophenone in 60 ml. of dry tetrahydrofurane is added dropwise, taking care that the temperature does not exceed -5° C. Thereafter the reaction mixture is stirred at 0° C. for 30 minutes and then at room temperature for two hours. The reaction mixture is decomposed with a 10% aqueous ammonium chloride solution, the phases are separated, and the aqueous phase is extracted with ether. The combined ethereal phases are washed to neutral with water, dried over anhydrous magnesium sulfate, filtered, and the solvent is distilled off in vacuo, after decoloring with activated carbon. Crystallization of the solid residue from a mixture of n-hexane and ethyl acetate yields 8.3 g. of the named compound, melting at 141° to 142° C.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.S(=O)(=O)(O)O>O>[CH:6]1([O:5][CH2:4][CH:3]=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(COC1CCCCC1)OC
Agent: O=S(=O)(O)O
Solvent: O
Product: O=CCOC1CCCCC1
Temperature: 100 °C
Yield: 51 %

Procedure:
Acidify a mixture of (2,2-dimethoxyethoxy)cyclohexane and water (30 mL) to a pH of 1.0 with sulfuric acid (9.0 M aqueous solution), and connect the mixture to a short-path distillation head. Reduce the pressure to 26.7 kPa and heat the mixture to 100° C. for 1 h. Cool the mixture to room temperature, then extract the aqueous layer with TBME (2×75 mL). Wash the combined organic layers with saturated aqueous NaHCO3 (75 mL) and saturated aqueous NaCl (75 mL). Dry the organic phase over MgSO4, filter, and concentrate the filtrate under reduced pressure to furnish the title compound (634 mg, 51% yield). 1H NMR (400 MHz, CDCl3): δ 9.73 (t, J=1.0 Hz, 1H), 4.06 (d, J=1.0 Hz, 2H), 3.31 (tt, J=9.2, 3.9 Hz, 1H), 1.95-1.89 (m, 2H), 1.79-1.68 (m, 2H), 1.57-1.50 (m, 1H), 1.39-1.20 (m, 5H).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4](=[CH2:28])[CH2:5][O:6][C:7]1[C:16]([C:17](=[O:19])[CH3:18])=[C:15]2[C:10]([C:11](=[O:27])[C:12]([CH3:26])=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:14]2)=[CH:9][CH:8]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40])[CH:34]=O>C(O)C.O>[CH3:26][C:12]1[C:11](=[O:27])[C:10]2[C:15](=[C:16]([C:17](=[O:19])[CH:18]=[CH:34][C:33]3[CH:36]=[C:37]([O:41][CH3:42])[C:38]([O:39][CH3:40])=[C:31]([O:30][CH3:29])[CH:32]=3)[C:7]([O:6][CH2:5][C:4]([CH3:3])=[CH2:28])=[CH:8][CH:9]=2)[O:14][C:13]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: C=C(C)COc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=C(C)COc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(=O)C=Cc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-(2-methylallyloxy)-8-acetyl-3-methylflavone (2.61 g, 0.0075 mol) and 3,4,5-trimethoxy-benzaldehyde (1.47 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.4 g of product m.p. 82-84° C., 1H-NMR (CDCl3) δ:1.76 (s, 3H); 2.20 (s, 3H); 3.82 (s, 3H); 4.62 (s, 2H); 5.05 (d, 2H, J=18 Hz); 6.95-7.10 (m, 3H); 7.09 (d, 1H); 7.10 (d, 1H, J=9 Hz); 7.31 (d, 1H, J=16 Hz); 7.40-7.45 (m, 3H); 7.55-7.58 (m, 2H); 7.31 (s, 2H); 8.32 (d, 1H, J=8.9 Hz).