Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]([N:6]1[CH2:11][CH2:10][S:9][CH2:8][CH2:7]1)=[O:5].[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29](O)=[O:30])=[CH:23]2>>[CH2:12]([C@H:3]([NH:2][C:29]([C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([Cl:19])=[CH:28][CH:27]=2)=[O:30])[C:4](=[O:5])[N:6]1[CH2:11][CH2:10][S:9][CH2:8][CH2:7]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCSCC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCSCC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
(S)-2-Amino-3-phenyl-1-thiomorpholin-4-yl-propan-1-one hydrochloride (2.6 mmol) and 5-chloro-1H-indole-2-carboxylic acid (2.6 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, washed with acid first, then base). The crude product was then triturated with 1:1 ether-hexanes and dried. Yield 1.03 g, 94%; HPLC (60/40) 8.74 minutes (99%); PBMS 428/430 (MH+, 100%);
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.Cl.N1CCCNCC1.[I-].[Na+].[CH3:19][S:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(O)C>[CH3:19][S:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:25][CH:24]=1)(=[O:21])=[O:22]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: C1CNCCNC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(CN2CCCNCC2)cc1
Temperature: 70 °C
Reaction time: 14 h
Yield: 65.4 %

Procedure:
A mixture of 120 mg of homopiperazine, 216 mg of homopiperazine dihydrochloride salt, 3 mL of ethanol was heated to 70° C. into a solution. To this solution were added sequentially 383 mg of sodium iodide and 250 mg of 4-(methylsulfonyl)benzyl bromide, followed by stirring at 70° C. for 14 hours. After the solution was cooled to room temperature, ethanol was removed under reduced pressure and 20 mL of aqueous 2N sodium hydroxide was added and the mixture was extracted with 20 mL×2 of ethyl acetate. The organic layers were combined, washed with 20 mL of aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 176 mg of 1-[4-(methylsulfonyl)benzyl]homopiperazine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:29][CH2:30][CH2:31][CH3:32])[N:25]([CH2:26][CH2:27][NH2:28])[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1>>[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:29][CH2:30][CH2:31][CH3:32])[N:25]([CH2:26][CH2:27][NH:28][C:9](=[O:11])[CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=3)[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)Cc1cccc(O)c1
Yield: 18.3 %

Procedure:
Using the general method of Example 97 3-hydroxyphenyl acetic acid (0.26 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.13 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-2-(3-hydroxyphenyl)acetamide as a white powder, m.p. 208-210° C. Analysis: Calculated for C23H26N6O2: %C, 66.01; %H, 6.26; %N, 20.08; Found: %C, 65.63; %H, 6.11; %N, 20.30. HRMS (EI) calcd for C23H26N6O2 (M+) 418.2117 found 418.2109.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.S1(=O)(=O)C2C=CC=CC=2C(=O)N1.[F:26][C:27]([F:32])([F:31])[C:28](O)=[O:29].FC(F)(F)S(O)(=O)=O>>[F:26][C:27]([F:32])([F:31])[C:28]([O:1][C:2]1[C:7]2[C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:29]
Reactant: O=C1NS(=O)(=O)c2cccc(O)c21
Reactant: O=C(O)C(F)(F)F
Agent: O=C1NS(=O)(=O)c2ccccc21
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1NS(=O)(=O)c2cccc(OC(=O)C(F)(F)F)c21

Procedure:
The specification describes a process for preparing 4-hydroxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide, a sweetener, from 1,2-benzisothiazol-3(2H)-one-1,1-dioxide by anodic oxidation in the presence of trifluoroacetic acid or trifluoromethanesulfonic acid and, optionally, in the presence of salts which increase the conductivity. The oxidation is effected in an anhydrous medium and the 4-trifluoroacetoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide formed as an intermediate when, for example, trifluoroacetic acid is used is decomposed with water to obtain the desired end product.
Reaction SMILES: [CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[CH:12]=[C:11]([CH3:13])[N:10]([C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[C:21]([N:23]2[C@H:32]([CH2:33][OH:34])[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[O:22])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].I[CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:50]([O:49][C:47](=[O:48])[CH2:46][O:20][C:18]1[CH:17]=[CH:16][C:15]([C:21]([N:23]2[C@H:32]([CH2:33][OH:34])[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[O:22])=[C:14]([N:10]2[C:11]([CH3:13])=[CH:12][C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:9]2)[CH:19]=1)[CH3:51]
Reactant: CCCCN(CCCC)C(=O)c1cc(C)n(-c2cc(O)ccc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Reactant: CCOC(=O)CI
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)C(=O)c1cc(C)n(-c2cc(OCC(=O)OCC)ccc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of 1-[5-hydroxy-2-((S)-3-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-phenyl]-5-methyl-1H-pyrazole-3-carboxylic acid dibutylamide (100 mg, 0.19 mmol) and potassium tert-butoxide (0.21 mL, 1 M, 0.21 mmol) in tetrahydrofuran (2 mL) was stirred at ambient temperature for 10 minutes. Ethyl 2-iodoacetate (0.027 mL, 0.23 mmol) was added and the mixture was stirred at ambient temperature for 1 hour. Ethyl acetate and aqueous HCl solution was added until the pH was about 7. The organic layer was dried over sodium sulfate and removed in vacuo. The crude material was purified by eluting through a short pad of silica gel column to afford the title compound (100 mg, 86% yield). MS (ESI) [m/e, (M+H)+]=605.3. 1H NMR (400 MHz, chloroform-d) δ ppm 6.30-7.41 (m, 8H), 2.68-5.46 (m, 18H), 2.20-2.61 (m, 3H), 0.70-1.74 (m, 15H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][CH:7]=1>>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:4][CH2:3][CH2:2][OH:1])=[CH:8][CH:7]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: NCCO
Product: OCCNCc1ccc(Cl)cc1

Procedure:
2-Hydroxyethylamine was reacted with 4-chlorobenzyl bromide according to Method B2a to give N-(4-chlorobenzyl)-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-(4-chlorobenzyl)-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-chloro-4-cyanophenyl isothiocyanate to give 2-(2-chloro-4-cyanophenylimino)-3-(4-chlorobenzyl)-1,3-thiazolidine.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:28]4[CH2:29][CH2:30][CH:25]([OH:24])[CH2:26][CH2:27]4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: OC1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCO
Product: OC1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1
Yield: 72.6 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (420 mg, 1.30 mmol, 1 wt), 4-hydroxypiperidine (268 mg, 2.60 mmol), absolute ethanol (17 ml, 40 vol), activated 3 Å molecular sieves (420 mg), titanium (IV) isopropoxide (1.94 ml, 4.62 vol) and STAB (2.34 g, 11.1 mmol) was reacted in accordance with the general procedure D. The isolated waxy solid was purified by preparative HPLC, eluting with acetonitrile/water/0.1% TFA as a gradient, to give the title compound as a white solid (380 mg, 73%). 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.86 (d, 2H), 4.02 (t, 2H), 3.75 (dt, 2H), 3.59-3.47 (m, 2H), 2.63 (t, 2H), 2.53 (br s, 4H), 2.35 (s, 2H), 2.33-2.25 (m, 2H), 2.13-1.96 (m, 6H), 1.93-1.83 (m, 2H), 1.82-1.76 (m, 4H), 1.72-1.59 (m, 3H), 1.47-1.29 (m, 3H).
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].CO[Na].[Br:8][C:9]1[CH:10]=[C:11]2C(=[CH:17][CH:18]=1)O[CH:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH2:13][C:12]2=[N:25][C:26]#[N:27].[CH3:28][OH:29]>>[Br:8][C:9]1[CH:10]=[C:11]2[C:12]3([O:4][N:3]([CH3:2])[C:26]([NH2:27])=[N:25]3)[CH2:13][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[O:29][C:28]2=[CH:17][CH:18]=1
Reactant: CNO
Reactant: N#CN=C1CC(c2ccccn2)Oc2ccc(Br)cc21
Reactant: CO
Agent: CO[Na]
Agent: Cl
Product: CN1OC2(CC(c3ccccn3)Oc3ccc(Br)cc32)N=C1N
Reaction time: 0.17 h
Yield: 40 %

Procedure:
To a solution of N-methyl-hydroxylamine hydrochloride (31 mg, 0.31 mmol) in MeOH (4 mL) was added MeONa (0.06 mL, 25% (Wt.) in MeOH), followed by 6-bromo-2-pyridin-2-yl-chroman-4-ylidene-cyanamide (100 mg, 0.31 mmol). After stirred for 10 minutes, the solvent was removed in vacuo. The residue was purified by preparative TLC to give 6-bromo-2′-methyl-2-(pyridin-2-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (45 mg, 40%). 1H-NMR (MeOD): 2.13 (m, 1H), 2.48 (m, 1H), 3.08 (m, 3H), 5.32 (m, 1H), 6.86 (m, 1H), 7.36 (m, 2H), 7.51 (m, 1H), 7.68 (m, 1H), 7.90 (m, 1H), 8.52 (m, 1H.).
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:2]([C:7]([O:9]N1C(=O)CCC1=O)=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].[NH2:27][C@H:28]([C:33]([NH:35][C@H:36]([C:41]([NH:43][C@H:44]([C:46]([NH:48][C@H:49]([C:55]([OH:57])=[O:56])[CH2:50][CH2:51][C:52](=[O:54])[NH2:53])=[O:47])[CH3:45])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31].C(N(CC)CC)C>CN(C)C=O>[NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[C@H:2]([C:7]([NH:27][C@H:28]([C:33]([NH:35][C@H:36]([C:41]([NH:43][C@H:44]([C:46]([NH:48][C@H:49]([C:55]([OH:57])=[O:56])[CH2:50][CH2:51][C:52](=[O:54])[NH2:53])=[O:47])[CH3:45])=[O:42])[CH2:37][CH:38]([CH3:39])[CH3:40])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:9])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.41 Grams of Z-Ile-OSu, the above-obtained H-Leu-Leu-Ala-Gln-OH and 0.36 ml of triethylamine were dissolved in 50 ml of dimethylformamide, then the mixture was stirred at a room temperature for 20 hours. After removal of dimethylformamide by distillation, 1N-citric acid was added to the residue, and crystals being precipitated were collected by filtration and washed with hot methanol to obtain 1.17 g of Z-Ile-Leu-Leu-Ala-Gln-OH.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH:41]1[C:53]2[CH:52]([CH2:54][O:55][C:56]([N:58]3[CH2:63][CH2:62][CH2:61][CH:60]([NH:64][C:65]4[C:70]([NH2:71])=[CH:69][N:68]=[C:67]5[N:72]([S:75]([C:78]6[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=6)(=[O:77])=[O:76])[CH:73]=[CH:74][C:66]=45)[CH2:59]3)=[O:57])[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]=2[CH:44]=[CH:43][CH:42]=1>CN(C=O)C>[CH:41]1[C:53]2[CH:52]([CH2:54][O:55][C:56]([N:58]3[CH2:63][CH2:62][CH2:61][CH:60]([NH:64][C:65]4[C:70]([NH:71][C:5](=[O:7])[CH2:4][CH:1]5[CH2:2][CH2:3]5)=[CH:69][N:68]=[C:67]5[N:72]([S:75]([C:78]6[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=6)(=[O:77])=[O:76])[CH:73]=[CH:74][C:66]=45)[CH2:59]3)=[O:57])[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]=2[CH:44]=[CH:43][CH:42]=1
Reactant: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Reactant: O=C(O)CC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC1CC1)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Cyclopropylacetic acid (0.300 g, 3.00 mmol), HATU (1.14 g, 3.00 mmol), and diisopropylethylamine (0.627 ml, 3.60 mmol) were added sequentially to a solution of 3-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (1.78 g, 3.00 mmol) in DMF (50 ml) at 25° C. The reaction mixture was stirred for 1.5 h at 25° C., then was concentrated under reduced pressure. The residue was partitioned between half-saturated NaHCO3 (125 ml) and EtOAc (2×150 ml). The combined organic layers were dried over Mg2SO4, filtered, and the filtrate was concentrated under reduced pressure to give crude 3-[1-benzenesulfonyl-5-(2-cyclopropyl-acetylamino)-1H-pyrrolo[2,3-b]pyridin-4-ylamino]-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester as a brown foam. LCMS (Method G, ESI): RT=1.24 min, m+H=676.4. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: C[Mg]Br.[Cl:4][C:5]1[CH:6]=[C:7]([NH:12][C:13](=[O:32])[C:14]([N:17]2[C:22](=[O:23])[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:20]([CH:30]=[O:31])[O:19][CH2:18]2)([CH3:16])[CH3:15])[CH:8]=[C:9]([Cl:11])[CH:10]=1.[Cl-].[NH4+].[C:35](OCC)(=O)C>CCOCC.O1CCCC1>[Cl:4][C:5]1[CH:6]=[C:7]([NH:12][C:13](=[O:32])[C:14]([N:17]2[C:22](=[O:23])[C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[C:20]([CH:30]([OH:31])[CH3:35])[O:19][CH2:18]2)([CH3:16])[CH3:15])[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C(=O)Nc1cc(Cl)cc(Cl)c1)N1COC(C=O)=C(c2ccccc2)C1=O
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)C1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cc(Cl)cc(Cl)c2)CO1

Procedure:
Methylmagnesium bromide (1.7 ml of a 3M solution in ether) was added dropwise to a stirred solution of N-(3,5-dichlorophenyl)-2-(6-formyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (1.0 g) in dry tetrahydrofuran under an inert atmosphere at -5° C. After 1 hour at that temperature, ammonium chloride solution (saturated) and ethyl acetate were added. The organic phase was washed (brine), dried (magnesium sulphate) and evaporated. The residue was purified by dry column chromatography on silica gel, eluting with dichloromethane/ethyl acetate to give N-(3,5-dichlorophenyl)-2[2,3-dihydro-6-(1-hydroxyethyl)-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl]-2-methylpropanamide (compound 123, 0.27 g) as a cream solid, m.p. 85-88° C.
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:32]([C:34]1[C@@H:39]([C:40]2[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=2)[N:38]2[N:48]=[C:49]([NH:51][CH2:52][C:53](O)=[O:54])[N:50]=[C:37]2[N:36]([C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[CH:57]=2)[C:35]=1[CH3:66])#[N:33].N.O1CCOCC1>CN(C=O)C>[C:32]([C:34]1[C@@H:39]([C:40]2[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=2)[N:38]2[N:48]=[C:49]([NH:51][CH2:52][C:53]([NH2:2])=[O:54])[N:50]=[C:37]2[N:36]([C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:63])[F:64])[CH:57]=2)[C:35]=1[CH3:66])#[N:33]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NCC(=O)O)nc2N1c1cccc(C(F)(F)F)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NCC(N)=O)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon protective gas and at 0° C., HATU (25 mg, 66 mmol, 3 eq.) and triethylamine (11 mg, 110 mmol, 5 eq.) were added to a solution of N-{(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}glycine (10.5 mg, 22 mmol) in DMF (1 ml). After the reaction mixture has thawed to RT, it was once more cooled to 0° C., and a 0.5 M solution of ammonia in dioxane (0.44 ml, 219 mmol, 10 eq.) was then added. The mixture was stirred for 2 h, during which time it gradually warmed to RT. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Kromasil C18 column, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (9.2 mg, 88% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([Cl:18])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)CCC(=O)OCc1ccccc1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
4-(benzyloxy)-4-oxobutanoic acid (6.16 g, 1 eq, from Example 1a) was dissolved in toluene (20 mL) and placed in a 300 mL round bottom flask, fitted with a condenser. While the reaction was stirred under inert atmosphere, thionyl chloride (5.30 g, 1.5 eq) was added. A few drops of DMF were also added and tire reaction mixture was heated to 35° C. for 45 minutes and then to 60° C. for 2 hours. The solution was concentrated to 6.71 g of brownish oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[S:20]>CN(C)C=O.O>[CH3:17][N:18]([CH3:22])[C:19](=[S:20])[O:12][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(F)ccc1O
Reactant: CN(C)C(=S)Cl
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)ccc1OC(=S)N(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a solution of methyl 5-fluorosalicylate (3.93 g, 23.1 mmol) in dry N,N-dimethylformamide (30 ml) was added sodium hydride (1.1 g, 50% oil dispersion). After hydrogen gas evolution had ceased, the mixture was cooled in an ice-bath, and dimethylthiocarbamoyl chloride (3.71 g, 30.0 mmol) was added. The mixture was stirred at 80° C. for one hour, cooled, and poured into water (100 ml). The product was extracted with diethyl ether (2×), and the combined organic extracts were washed with water, 5% aqueous potassium hydroxide, water, dried (sodium sulfate), and evaporated. The solid obtained was recrystallized from diethyl ether-hexane to afford 3.16 g (53%) of O-2-carbomethoxy-4-fluorophenyl dimethylthiocarbamate. The 90 MHz NMR spectrum in chloroform-d was in accord with the desired structure.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([S:25][C:26]1[C:34]([N:35]([CH3:37])[CH3:36])=[CH:33][C:29]3[O:30][CH2:31][O:32][C:28]=3[CH:27]=1)[N:6]2[CH2:11][CH2:12][CH2:13][N:14]1C(=O)C2C(=CC=CC=2)C1=O.O.NN.CO>C(Cl)Cl>[NH2:14][CH2:13][CH2:12][CH2:11][N:6]1[C:5]([S:25][C:26]2[C:34]([N:35]([CH3:37])[CH3:36])=[CH:33][C:29]3[O:30][CH2:31][O:32][C:28]=3[CH:27]=2)=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH2:1]
Reactant: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCN1C(=O)c3ccccc3C1=O)OCO2
Agent: NN
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCN)OCO2
Yield: 80.4 %

Procedure:
2-(3-(6-Amino-8-(6-(dimethylamino)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-9-yl)propyl)isoindoline-1,3-dione (0.72 g, 1.38 mmol), hydrazine hydrate (2.86 g, 2.78 mL, 20.75 mmol), in CH2Cl2:MeOH (4 mL:28 mL) was stirred for 2 h at rt. The mixture was dried under reduced pressure and the residue purified by column chromatography (CH2Cl2:MeOH—NH3(7N), 20:1) to give 430 mg (80%) of the titled compound. 1H NMR (500 MHz, CDCl3): δ 8.33 (s, 1H), 6.77 (s, 1H), 6.49 (s, 1H), 5.91 (s, 2H), 5.85 (br s, 2H), 4.30 (t, J=6.9 Hz, 2H), 2.69 (s, 6H), 2.65 (t, J=6.5 Hz, 2H), 1.89-1.95 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 154.5, 153.1, 151.7, 148.1, 147.2, 146.4, 144.8, 120.2, 120.1, 109.3, 109.2, 101.7, 45.3, 45.2, 40.9, 38.6, 333; HRMS (ESI) m/z [M+H]+ calcd. for C17H22N7O2S, 388.1556. found 388.1544.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=3)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[OH-].[Li+]>O1CCCC1.CO>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[O:6][C:7]=3[CH3:26])=[CH:13][CH:14]=2)=[N:19][CH:20]=1
Reactant: COC(=O)c1cc(COc2ccc(-c3ccc(OC)cn3)cc2)c(C)o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-[4-(5-methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carboxylic acid methyl ester (52) (70 mg) and 1M aqueous lithium hydroxide (1 mL) in tetrahydrofuran/methanol (2:1 by volume) (12 mL) was stirred at room temperature for 16 hours. The reaction mixture was acidified to between pH6 and pH7, and partitioned between ethyl acetate and water. The organic phase was separated, washed with brine and dried (MgSO4). After removal of the solvent, the residue was purified by HPLC. Compound 53 was obtained as a solid (2.5 mg). LC/MS System A: Rt=2.90 mins, m/z (ES+) 340 ((M+H) for C19H17NO5).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br.O>CN(C)C=O>[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][N:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:10][CH:11]=1)[C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17]
Reactant: Fc1cccc(CBr)c1
Reactant: O=C(Nc1ccc(OCCN2CCCC2)cc1)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(C1CCCCC1)N(Cc1cccc(F)c1)c1ccc(OCCN2CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of cyclohexanecarboxylic acid (4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-amide (0.250 g, 0.79 mmol) in 5 mL N,N-dimethylformamide at 0° C. was added sodium hydride (0.041 g of a 60% dispersion in mineral oil, 1.03 mmol). The reaction mixture was stirred at 0° C. for 5 minutes and 3-fluorobenzyl bromide (0.117 mL, 0.95 mmol) was added. The reaction mixture was stirred at room temperature for 24 hr. and water was added. The aqueous solution was washed with ethyl acetate (2×). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated. Medium pressure silica gel chromatography (methylene chloride to 5% methanol/methylene chloride) afforded the title compound. MS 425.2 (M+1)+