Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:19]=[C:18]3[C:12]([CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17]3)=[N:11]2)=[CH:6][CH:5]=1)=[O:3].FC(F)(F)C(O)=O>ClCCl.CO>[N:11]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:2]([NH2:1])=[O:3])=[CH:5][CH:6]=2)[CH:19]=[C:18]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][C:12]=12
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(C(N)=O)cc3)nc2CC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(-n2cc3c(n2)CCNCC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl 2-[4-(aminocarbonyl)phenyl]-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 36) (167 mg, 0.47 mmol) in dichloromethane (14 ml) was added trifluoroacetic acid (7 ml). The resulting mixture was stirred at room temperature, under argon, for 2 hours and then diluted with methanol. Reaction was purified by SCX, eluting with methanol and then 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (D37). MS (ES+) m/e 257 [M+H]+.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=O.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[C:13]=1[NH:20][NH2:21]>CN(C1C=CN=CC=1)C.CN1C(=O)CCC1>[I:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]2[N:20]([C:13]3[C:14]([F:19])=[CH:15][C:16]([F:18])=[CH:17][C:12]=3[F:11])[N:21]=[CH:4][C:3]=12
Reactant: NNc1c(F)cc(F)cc1F
Reactant: O=Cc1c(I)ccnc1F
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Product: Fc1cc(F)c(-n2ncc3c(I)ccnc32)c(F)c1
Temperature: 185 °C
Yield: 16.8 %

Procedure:
To a 15 mL pressure bottle was added 2-fluoro-4-iodonicotinaldehyde (530 mg, 2.112 mmol), (2,4,6-trifluorophenyl)hydrazine (359 mg, 2.215 mmol), DMAP (53 mg, 0.434 mmol), and anhydrous NMP (4 mL). The reaction mixture was flushed with argon, securely capped, and heated to 185° C. for 1.75 h. The reaction mixture was worked up according to the procedure described in Intermediate 69A and the product was purified by Biotage Silica gel chromatography using a 40 g Thompson Single Step™ silica cartridge with a linear gradient from 100% hexanes to 100% CH2Cl2 over 14 column volumes to give 133 mg (16.8%) of the title compound as a yellow solid. LC/MS (Condition B): ret. T=3.7 min, (M+H)+ 375.90 and 230 mg (27.6%) of the hydrazone intermediate as a pale yellow solid, LC/MS (Condition B): ret. T=3.7 min, (M+H)+ 395.90.
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=[C:6]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:9]2=[O:15])[CH:7]=1.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1B(O)O>>[O:15]=[C:9]1[NH:10][C:11](=[O:14])[CH:12]=[CH:13][N:8]1[C:6]1[CH:7]=[C:2]([C:34]2[S:33][CH:37]=[CH:36][CH:35]=2)[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=1
Reactant: OB(O)c1cccs1
Reactant: COc1c(Br)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CNS(C)(=O)=O
Product: COc1c(-c2ccc3c(c2)CC=C3CNS(C)(=O)=O)cc(-n2ccc(=O)[nH]c2=O)cc1-c1cccs1
Yield: 32 %

Procedure:
The product from Example 93, Part A (26.5 mg, 0.051 mmol) was reacted with thiophen-2-yl boronic acid (8.3 mg, 0.065 mmol) as described in Example 93, Part B to give the title compound as an off-white solid (8.6 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ 11.47 (s, 1H) 7.86 (d, J=7.72 Hz, 2H) 7.55-7.78 (m, 5H) 7.50 (t, J=6.25 Hz, 1H) 7.38 (d, J=2.57 Hz, 1H) 7.16-7.21 (m, 1H) 6.58 (s, 1H) 5.69 (d, J=7.72 Hz, 1H) 4.19 (d, J=4.78 Hz, 2H) 3.48 (s, 2H) 3.30 (s, 3H) 2.96 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=2)[S:5][CH:6]=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>N1C=CC=CC=1.CCOC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]([C:7]2[C:8](=[O:14])[N:9]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:22])[C:10](=[O:13])[NH:11][CH:12]=2)[S:5][CH:6]=1
Reactant: Cc1csc(-c2c[nH]c(=O)[nH]c2=O)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1csc(-c2c[nH]c(=O)n(C(=O)c3ccccc3)c2=O)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 54.1 %

Procedure:
5-(4-methyl-1,3-thiazol-2-yl)-2,4(1H,3H)-pyrimidinedione (Prep41, 300 mg, 0.760 mmol) suspended in dry Pyridine (3 ml) was slowly added to a stirring solution of BENZOYL CHLORIDE (0.265 ml, 2.280 mmol) in Pyridine (1 mL) under nitrogen atmosphere. The resulting yellow solution was stirred at rt for 7 hours. Water was added (3 mL) and the mixture was extracted with EtOAc (10 mL). The organic was washed with NH4Cl saturated aqueous solution (2×2 mL) then with NaHCO3 aqueous saturated solution (1×3 mL), dried (Na2SO4, vacuo) to afford a yellow solid that was diluted in EtOAc (20 mL) and washed again with NaHCO3 aqueous saturated solution (2×5 mL), dried (Na2SO4, vacuo) to afford the title compound as a yellow solid (274 mg, 0.411 mmol) used in the next reaction step without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[NH:15][C:14]4[CH:19]=[N:20][N:21]([CH3:22])[C:13]=4[C:12](=[O:23])[C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.COC1C=CC(C2C3C(=O)C4N(C)N=CC=4NC=3C=CC=2)=CC=1>>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[NH:15][C:14]4[CH:19]=[N:20][N:21]([CH3:22])[C:13]=4[C:12](=[O:23])[C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ccc3[nH]c4cnn(C)c4c(=O)c3c2)c1
Agent: COc1ccc(-c2cccc3[nH]c4cnn(C)c4c(=O)c23)cc1
Product: Cn1ncc2[nH]c3ccc(-c4cccc(O)c4)cc3c(=O)c21

Procedure:
The title compound was prepared according to the procedure of step 4 in EXAMPLE 38 using 7-(3-methoxyphenyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (EXAMPLE 40, step 2), instead of 8-(4-methoxyphenyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one.
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[Na].CS([CH2:19][CH2:20][CH2:21][C@H:22]([CH3:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])(=O)=O.O>CS(C)=O>[CH3:29][C@H:22]([CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH2:21][CH2:20][CH2:19][N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3]
Reactant: CC(C)=CCC[C@@H](C)CCCS(C)(=O)=O
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)=CCC[C@@H](C)CCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
To a suspension of sodium theobromine (4.05 g, 20.0 mmol) in dimethylsulfoxide (50 mL) was added 1-methanesulfonyl-4-(R)-methyl-8-methylnon-7-ene and the reaction stirred for 16 hours at 60° C. The mixture was then poured into water (100 mL) and extracted with ethyl acetate (100 mL, 2×50 mL). The organic portions were combined, dried using magnesium sulfate and the solvent evaporated to give a residue which was purified by column chromatography using ethyl acetate/hexane to yield 1.70 g (28% yield) 1-(4-(R)-Methyl-8-methylnon-7-enyl)-3,7-dimethylxanthine (inventive compound no. 2536R) as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][O:9][CH2:10][CH3:11])[CH3:2].C[Al](C)C.[Cl:16][C:17]1[CH:37]=[CH:36][C:20]2[C:21](=[O:35])[C:22]3[C:29]([C:30](OCC)=[O:31])=[N:28][NH:27][C:23]=3[C:24](=[O:26])[NH:25][C:19]=2[CH:18]=1>C1(C)C=CC=CC=1>[Cl:16][C:17]1[CH:37]=[CH:36][C:20]2[C:21](=[O:35])[C:22]3[C:29]([C:30](=[O:31])[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH2:7][CH2:8][O:9][CH2:10][CH3:11])=[N:28][NH:27][C:23]=3[C:24](=[O:26])[NH:25][C:19]=2[CH:18]=1
Reactant: CCOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reactant: CCOCCNCCOCC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCOCCN(CCOCC)C(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reaction time: 0.33 h
Yield: 44.7 %

Procedure:
Bis-(2-ethoxyethyl)amine (560 μL, 3.13 mmol) was added to a solution of trimethylaluminum in toluene (1.56 mL, 3.13 mmol) and the solution was stirred for 20 minutes. A portion (424 μL) of the resulting solution was added to a solution of 7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (100 mg, 0.313 mmol) in toluene (780 μL). The resulting solution was stirred for 4.5 hours at room temperature and then quenched with aqueous hydrochloric acid (1.5 mL, 1N) and water (20 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL) and the organic layers were concentrated on a rotary evaporator. The crude product was purified by flash chromatography eluting with chloroform:2-propanol (99:1-80:20) to give the title compound (60.8 mg, 45% yield, m.p. 202° C.).
Reaction SMILES: [C-]#N.[Na+].[CH3:4][S:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:16]=1.O>CN(C)C=O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]([C:10]([C:9]2[CH:12]=[CH:13][C:6]([S:5][CH3:4])=[CH:7][CH:8]=2)=[O:11])[CH2:22][C:23](=[O:25])[CH3:24])=[CH:19][CH:20]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: CC(=O)C=Cc1ccc(Cl)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(C(=O)C(CC(C)=O)c2ccc(Cl)cc2)cc1
Temperature: 35 °C
Yield: 48.3 %

Procedure:
Sodium cyanide (90 mg, 1.87 mmol) was added to a solution of 4-(methylthio)benzaldehyde (300 mg, 1.97 mmol) in N,N-dimethylformamide (2 ml). While stirring the resulting mixture at 30-40° C., a solution of 4-(4-chlorophenyl)-3-buten-2-one (370 mg, 1.97 mmol) in N,N-dimethylformamide (3 ml) was dropped. The thus-obtained mixture was then stirred at the same temperature for 90 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed successively with water and brine, and was then dried over anhydrous sodium sulfate. The solvent was distilled off and the thus-obtained brown oil (762 mg) was separated and purified by preparative thin-layer chromatography on silica gel [developing solvent: hexane/diethyl ether (2/1)], whereby the title compound was obtained as a pale yellow oil (317 mg, 48.3%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][N:10]=2)=[CH:4][C:3]=1[N:20]1[C:24](=[O:25])[CH:23]([CH3:26])[N:22]([CH2:27][C:28]([OH:30])=[O:29])[C:21]1=[O:31].S(=O)(=O)(O)O.[CH3:37]O>>[CH3:37][O:29][C:28](=[O:30])[CH2:27][N:22]1[CH:23]([CH3:26])[C:24](=[O:25])[N:20]([C:3]2[CH:4]=[C:5]([CH2:8][C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12](=[O:19])[NH:11][N:10]=3)[CH:6]=[CH:7][C:2]=2[F:1])[C:21]1=[O:31]
Reactant: CO
Reactant: CC1C(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C(=O)N1CC(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)CN1C(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C(=O)C1C
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To a solution of {3-[2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-phenyl]-5-methyl-2,4-dioxo-imidazolidin-1-yl}-acetic acid (36A)(0.04 g, 0.094 mmol) in methanol (4 ml) was added concentrated sulfuric acid (1 ml) and stirred at 70° C. for 90 minutes before being cooled to room temperature. The reaction mixture was then concentrated in vacuo, diluted with water (10 ml) an extracted with ethyl acetate (2×10 ml). The organic layer was then dried over sodium sulfate and concentrated in vacuo to afford a colourless oil. Single peak in LC-MS, (52 mg, 95% purity) and required no further purification; m/z (LC-MS, ESP), RT=3.24 mins (M+H) 439;
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]1)=[O:7])=[O:2].[C:24](O)([C:26](F)(F)F)=[O:25].C1OC1C>C(Cl)Cl>[OH:25][CH:24]([CH3:26])[CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:6]([C:5]2[CH:4]=[C:3]([CH:23]=[CH:22][CH:21]=2)[CH:1]=[O:2])=[O:7])[CH2:13][CH2:12]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(C=O)c2)CC1
Agent: CC1CO1
Solvent: ClCCl
Product: CC(O)CN1CCN(C(=O)c2cccc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.5 %

Procedure:
To a solution of tert-butyl 4-(3-formylbenzoyl)piperazine-1-carboxylate 21 (700 mg, 2. 2 mmol) in DCM (5 mL) was added TFA (1.75 mL, 1.54 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3 h. After 3 h, RM was washed with 10% sodium bicarbonate solution and concentrated. The crude material was dissolved in methanol (4 mL) and propylene oxide (892 mg, 15.3 mmol) was added. The reaction was heated at 55° C. for 15 h. TLC analysis indicated complete consumption of starting material. The reaction mixture was concentrated and purification of crude material by column chromatography (3% MeOH/DCM, Silica (230-400)) afforded product as white sticky solid (100 mg, 16.4%).
Reaction SMILES: [CH2:1]([NH2:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:24](OCC)(=[O:28])[CH:25]([CH3:27])[OH:26]>>[CH2:1]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[OH:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCCN
Reactant: CCOC(=O)C(C)O
Product: CCCCCCCC/C=C\CCCCCCCCCCCCNC(=O)C(C)O
Temperature: 130 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A one-liter, 3-neck flask equipped with a stirrer, thermometer, Dean-Stark receiver and condenser was charged with erucyl amine (320 grams; 1.0 mol), and ethyl lactate (130 grams; 1.1 mol) and stirred at 130° C. for 8 hours under a nitrogen atmosphere. The reaction was followed by total amine value and infrared spectrum analyses. The reaction mixture was then stripped at 135° C., 30 mmHg vacuum for 30 minutes to afford 368 g (94% yield) of N-erucyl lactamide. This product had a total amine value of 1.6; a hydroxy value of 139.8 and a melting point of 50° C. The structure of this product was confirmed by infrared analysis showing disappearance of the absorption band at about 5.7 microns for ethyl lactate and the presence of a strong amide absorption band at about 6.15 microns, along with hydroxy absorption band at about 2.0 to 3.1 microns.
Reaction SMILES: ClC1C(Cl)=CC(N[C:13](=O)[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:18][CH:17]=2)=CC=1C(O)=O.[NH2:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[NH2:46])[C:39]([O:41][CH3:42])=[O:40].C(N(CC)CC)C>ClCCl>[C:28]1([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][C:13]3[NH:35][C:36]4[CH:37]=[C:38]([C:39]([O:41][CH3:42])=[O:40])[CH:43]=[CH:44][C:45]=4[N:46]=3)=[CH:17][CH:18]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(CCc1ccc(OCCCCCc2ccccc2)cc1)Nc1cc(Cl)c(Cl)c(C(=O)O)c1
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2nc(CCc3ccc(OCCCCCc4ccccc4)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the compound prepared in Reference Example 3 which prepared by the same procedure as described in Example 3 using the compound prepared in Reference Example 2 (150 mg) in dichloromethane (5 mL) was added methyl 3,4-diaminobenzoate (160 mg) and triethylamine (0.34 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. To a solution of the obtained residue in toluene (10 mL) was added p-toluenesulfonate (50 mg). The reaction mixture was refluxed overnight. Saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was washed with diisopropyl ether to give the compound of the present invention (99 mg) having the following physical data.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC.O>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:11]=[CH2:12])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.6 %

Procedure:
0.5 g of 2-chloro-5-nitro-pyridine (3.15 mmol), 1.2 g of tributyl-vinyl-stannane (3.78 mmol), 0.036 g of tetrakistriphenylphosphinpalladium(0) (0.03 mmol), and 0.024 g of triphenylphosphin (0.09 mmol) were dissolved in 20 ml of toluene and stirred for 2 h under reflux. Upon cooling to room temperature, 10 ml of water were added, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The crude product was purified via silica gel chromatography with cyclohexane/ethyl acetate (10%). Fractions containing the product were combined, the solvent evaporated to yield 0.528 g of the desired product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:3][CH2:2]1.[Cl:30][C:31]1[CH:32]=[N:33][C:34](I)=[N:35][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:30][C:31]1[CH:32]=[N:33][C:34]([N:1]2[CH2:6][CH2:5][CH:4]([O:7][C:8]3[S:9][C:10]4[CH:16]=[C:15]([CH:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)[CH:14]=[CH:13][C:11]=4[N:12]=3)[CH2:3][CH2:2]2)=[N:35][CH:36]=1
Reactant: Clc1cnc(I)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3nc(OC4CCNCC4)sc3c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3nc(OC4CCN(c5ncc(Cl)cn5)CC4)sc3c2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
To a solution of tert-butyl 4-(2-(piperidin-4-yloxy)benzo[d]thiazol-6-yl)piperidine-1-carboxylate (337 mg, 0.807 mmol) and 5-chloro-2-iodopyrimidine (213 mg, 0.888 mmol) in DMF (10 mL) was added potassium carbonate (335 mg, 2.421 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was cooled to rt, diluted with water (30 mL), and extracted with EtOAc (3×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was recrystallized from EtOAc to afford tert-butyl 4-(2-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)benzo[d]thiazol-6-yl)piperidine-1-carboxylate (133 mg, 0.251 mmol, 31% yield) as an off white solid. LCMS (m/z)=531 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:21][OH:22])[CH2:3][O:4][C:5]1[C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:19])[C:9]=2[C:8]([F:20])=[CH:7][CH:6]=1.Cl[CH2:24][CH2:25][C:26](Cl)=[O:27].C(=O)([O-])[O-].[K+].[K+].[C:35]([C:39]1C=C(C)C=C(C(C)(C)C)[C:40]=1[OH:50])(C)(C)C>ClCCl.C(#N)C>[C:26]([O:1][CH:2]([CH2:3][O:4][C:5]1[C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:19])[C:9]=2[C:8]([F:20])=[CH:7][CH:6]=1)[CH2:21][O:22][C:40](=[O:50])[CH:39]=[CH2:35])(=[O:27])[CH:25]=[CH2:24]
Reactant: O=c1c2ccccc2sc2c(OCC(O)CO)ccc(F)c12
Reactant: O=C(Cl)CCCl
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: C=CC(=O)OCC(COc1ccc(F)c2c(=O)c3ccccc3sc12)OC(=O)C=C
Temperature: 81 °C
Reaction time: 6 h
Yield: 622.4 %

Procedure:
4-(2,3-dihydroxy-propoxy)-1-fluoro-thioxanthen-9-one (2.9 g, 9 mmol), 3-chloropropionyl chloride (9.5 g, 75 mmol), potassium carbonate (10.4 g, 75 mmol) and 2,6-di-tert-butyl-4-methylphenol (0.1 g, 0.00045 mol) were added to acetonitrile (35 mL). The reaction mixture was heated at 81° C. and stirred for 6 hours. After cooling down to room temperature, dichloromethane (200 mL) was added and the reaction mixture was extracted with distilled water (200 mL). The organic layer was separated, dried over MgSO4 and evaporated under reduced pressure. The product was purified on a Prochrom LC 80 Column using dichloromethane/ethyl acetate (98/2) as eluent and Kromasil Si60A 10 μm as packing material, to yield 1.2 g of acrylic acid 2-acryloyloxy-3-(1-fluoro-9-oxo-9H-thioxanthen-4-yloxy)-propyl ester.
Reaction SMILES: [CH2:1]([C:4]1([CH2:29][CH2:30][O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:5]1=[O:28])[CH:2]=C.I([O-])(=O)(=O)=[O:43].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:6]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[C:5](=[O:28])[C:4]([CH2:1][CH:2]=[O:43])([CH2:29][CH2:30][O:31][Si:32]([CH:33]([CH3:35])[CH3:34])([CH:39]([CH3:40])[CH3:41])[CH:36]([CH3:38])[CH3:37])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCC1(CCO[Si](C(C)C)(C(C)C)C(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](OCCC1(CC=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O)(C(C)C)C(C)C
Reaction time: 0.42 h

Procedure:
To a solution of 1.28 g (2.08 mmol) of (5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2-(triisopropylsilyloxy)ethyl)piperidin-2-one (Example 69, Step A, mixture of diastereomers) in THF (50 mL) and water (17.5 mL) was added a catalytic amount of osmium tetroxide. After 25 min, 1.34 g (6.25 mmol) of sodium periodate was added. The resulting light brown slurry was stirred for 19 h and then was filtered through a fritted funnel. The filtrate was partially concentrated under reduced pressure, then was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with saturated aqueous sodium thiosulfate and then saturated aqueous sodium chloride. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. The crude title compound (mixture of C-3 epimers) was used directly in the next step.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]([OH:14])([CH3:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[H-].[Na+].[H][H].[Cl:19][C:20]1[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[C:23]([N:29]=[C:30]=[O:31])=[C:22]([CH:32]([CH3:34])[CH3:33])[CH:21]=1>O1CCCC1>[Cl:19][C:20]1[CH:21]=[C:22]([CH:32]([CH3:34])[CH3:33])[C:23]([NH:29][C:30]([NH:1][S:2]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([OH:14])([CH3:12])[CH3:13])[CH:6]=2)(=[O:3])=[O:4])=[O:31])=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:25]=1
Reactant: CC(C)(O)c1cccc(S(N)(=O)=O)c1
Reactant: [H][H]
Reactant: CC(C)c1cc(Cl)cc(C(C)C)c1N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc(Cl)cc(C(C)C)c1NC(=O)NS(=O)(=O)c1cccc(C(C)(C)O)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-(3-aminosulfonylphenyl)-propan-2-ol (26.5 grams) in tetrahydrofuran was added sodium hydride (5.2 grams of a 60% dispersion in mineral oil) in several portions. Once hydrogen evolution had subsided, 4-chloro-2,6-diisopropylphenylisocyanate (30.8 grams) was added in one portion, and the resulting mixture was heated to reflux for twelve hours. The mixture was then cooled to room temperature and concentrated in vacuo. The resulting foam was dissolved in water, made basic with 1N sodium hydroxide and extracted with two portions of a 1:1 ration of ether/hexane. The aqueous layer was acidified with 1N hydrochloric acid, and the resulting white solid was filtered, washed with water and dried. This afforded 50 grams of a white solid which was recrystallized from wet ethyl acetate/hexane afforded the title compound, melting point 160.5-162.0° C.