Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C@@H:15]1[C@:19]([Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([OH:20])[C@@H:18]([CH2:38][O:39][C:40]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[O:17][C@H:16]1[N:63]1[C:72]2[N:71]=[CH:70][N:69]=[C:67]([NH2:68])[C:66]=2[N:65]=[CH:64]1)=[O:7])#[N:2].[C:73](C1NN=NN=1)(=[O:80])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1.CC(C)=O.C(Cl)Cl.C(=O)(O)[O-].[Na+]>CC#N.CCOC(C)=O.O>[C:73]([NH:68][C:67]1[C:66]2[N:65]=[CH:64][N:63]([C:72]=2[N:71]=[CH:70][N:69]=1)[C@@H:16]1[O:17][C@H:18]([CH2:38][O:39][C:40]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C@@:19]([Si:21]([C:34]([CH3:35])([CH3:36])[CH3:37])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([OH:20])[C@H:15]1[O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])=[O:7])(=[O:80])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@H](OCCCCCNC(=O)OCCC#N)[C@@]2(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(c1ccccc1)c1nnn[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)[C@H](OCCCCCNC(=O)OCCC#N)[C@@]2(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of compound 54 (0.25 g, 0.25 mmol) and benzoyl-tetrazole (0.09 g, 0.50 mmol) in anhydrous CH3CN (0.5 mL) was stirred in a preheated bath at 65° C. for 1.5 h. After this time, the TLC (10% CH3COCH3/CH2Cl2) that the reaction was complete. The reaction mixture was cooled to room temperature and taken up in EtOAc (30 mL) ,washed with aq saturated sodium bicarbonate solution (2×15 mL) and water (15 mL) dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using 10% CH3COCH3/CH2Cl2 as the eluent and the appropriate fractions were combined and concentrated to give a colorless foam, yield (0.105 g, 50%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc([N+](=O)[O-])cc2Br)cc1
Temperature: 90 °C
Yield: 100 %

Procedure:
A mixture of 2-bromo-1-fluoro-4-nitrobenzene (2.20 g, 10 mmol), 4-hydroxybenzonitrile (1.31 g, 11 mmol), and cesium carbonate (3.58 g, 11 mmol) in DMSO (20 mL) was heated at 90° C. for 2 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 3.19 g (110%) of the title compound.
Reaction SMILES: C([C:5](C(C)(C)C)([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:37])[CH2:17][NH:18][C:19]([C:21]2[S:22][C:23]3[CH2:24][NH:25][CH:26](C(OC(C)(C)C)=O)[CH2:27][C:28]=3[N:29]=2)=[O:20])=[CH:12][C:11]=1[O:38][CH2:39][C:40]([O-:42])=[O:41])[C:6]([O-:8])=[O:7])(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[N:29]1[C:28]2[CH2:27][CH2:26][NH:25][CH2:24][C:23]=2[S:22][C:21]=1[C:19]([NH:18][CH2:17][CH:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:5][C:6]([OH:8])=[O:7])=[C:11]([O:38][CH2:39][C:40]([OH:42])=[O:41])[CH:12]=1)[OH:37])=[O:20]
Reactant: CC(C)(C)OC(=O)C1Cc2nc(C(=O)NCC(O)c3ccc(OC(C(=O)[O-])(C(C)(C)C)C(C)(C)C)c(OCC(=O)[O-])c3)sc2CN1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Product: O=C(O)COc1ccc(C(O)CNC(=O)c2nc3c(s2)CNCC3)cc1OCC(=O)O
Yield: 77.8 %

Procedure:
To the solution of the compound prepared in (a) (115.3 mg, 0.174 mmole) in anisole (0.5 ml) was added trifluoroacetic acid (2.0 ml) at 0° C. Crystals were deposited by the addition of isopropyl ether at 0° C., collected by filtration, and lyophilized to give 82.1 mg of a crude product, which was purified on a LH column (50% methanol) to give 76.6 mg of the title compound as a colorless crystal (yield, 77.8%).
Reaction SMILES: [O:1]=[C:2]1[C@H:8]2[CH2:9][C@H:4]([CH2:5][CH2:6][C@@H:7]2[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:3]1.[CH3:17][O-:18].[Na+].Cl>CO>[OH:3][C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:8]([C:2]([O:18][CH3:17])=[O:1])[CH2:9]1
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@H]2C[C@@H]1C(=O)O2
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1C[C@@H](O)CC[C@@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
tert-butyl (1S,2S,5S)-7-oxo-6-oxabicyclo[3.2.1]octane-2-carboxylate (5.65 g, 25.0 mmol) was suspended in methanol (20 mL). To that suspension was added a 25 wt % solution of sodium methoxide in methanol (52 mL) and the reaction mixture was stirred at rt for 2 h. Then it was cooled into an ice-water bath and neutralized with a 4 M HCl solution to pH 6. After removing the volatiles, brine was added (50 mL) and the solution was extracted with ethyl acetate (3×40 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide the desired product (5.70 g, 88.4% yield). LCMS: m/z 281.1 (M+Na)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].C(C1C=NC(N2CCC(OC3SC4C=C(C5CCNCC=5)C=CC=4N=3)CC2)=NC=1)CC>>[N:26]1([C:24]2[CH:23]=[CH:22][C:20]3[N:21]=[C:17]([O:16][CH:13]4[CH2:12][CH2:11][N:10]([C:7]5[N:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][N:6]=5)[CH2:15][CH2:14]4)[S:18][C:19]=3[CH:25]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)nc1
Agent: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)nc1
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(N5CCNCC5)cc4s3)CC2)nc1

Procedure:
Compound 12B was synthesized from Compound 12A in a similar manner to the procedure described for Compound 1E. 1H NMR (500 MHz, chloroform-d) δ ppm 8.17 (2H, s), 7.57 (1H, d, J=8.8 Hz), 7.18 (1H, d, J=2.5 Hz), 7.02 (1H, dd, J=8.8, 2.5 Hz), 5.36-5.44 (1H, m), 4.21 (2H, ddd, J=13.3, 6.8, 3.9 Hz), 3.62-3.73 (2H, m), 3.15-3.25 (4H, m), 3.05-3.15 (4H, m), 2.41 (2H, t, J=7.6 Hz), 2.11-2.23 (2H, m), 1.93 (2H, dddd, J=12.7, 8.4, 8.2, 4.0 Hz), 1.53-1.64 (2H, m), 0.92-0.98 (3H, m). LC/MS (m/z)=439 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(N(CC)CC)C.[C:17]([O:24][CH2:25]Cl)(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CN(C)C=O>[C:17]([O:24][CH2:25][N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CCCCCC(=O)OCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCC(=O)OCn1cc(F)c(=O)[nH]c1=O
Yield: 40.5 %

Procedure:
Using a reactor similar to that used in Example 1, 3.90 g (0.03 mol) of 5-fluorouracil was dissolved in 50 ml of dimethylformamide. Then, 3.0 g of triethylamine was added to this solution. To the mixture was added dropwise 4.73 g (0.0287 mol) of caproyloxymethyl chloride. The mixture was reacted for 3 hours at 50° C. After completion of the reaction, the reaction liquid was filtered to remove the precipitated triethylamine hydrochloride and then the dimethylformamide was removed by distillation from the filtrate. Next, 50 ml of chloroform was added to the residue and the mixture was stirred and filtered to remove insoluble unreacted 5-fluorouracil. The chloroform phase was washed with water and then dried. By removing the chloroform by distillation, 3.0 g of 1-caproyloxymethyl-5-fluorouracil was obtained as white crystals having a melting point of 95°~96° C. in a yield of 38.7%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][C:18]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:12][CH:11]=1.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[S:17][C:18]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:14][CH:15]=1)=[O:8]
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: O=C(O)c1ccco1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccco4)cc3)sc2c1
Temperature: 25 °C

Procedure:
First Route: 2-Furoic acid (1.85 gms, 16.5 mmole) was dissolved in anhydrous methylene chloride (30 mls), to which solution was added a suspension of 2-(4-amino-phenyl)-6-methyl benzothiazole (4.76 g., 16.5 mmole) and N-methyl morpholine (2.0 g., 16.5 mmole) in methylene chloride (30 mls, at room temperature). Then, 1-hydroxy-benzotriazole hydrate (2.67 g., 16.5 mmole) and 1-(3-dimethyl amino propyl)-3-ethyl carbodiimide hydrochloride (4.75 g., 16.5 mmole) were added at room temperature. More methylene chloride (20 ml.) was added with stirring at room temperature, and the reaction maintained overnight. The initial clear reaction solution changed to a turbid solution. More methylene chloride (10 ml.) was added to the product mixture, which was then extracted with 1N HCl to separate a solid. The solid was filtered and washed with water. The product solid was crystallized from large amount of MeOH to yield 2.19 gm. (33.1%). mp. 238-240° C. 1R and 13C NMR were consistent with the expected product. TLC showed one spot (5% MeOH—CH2Cl2 as developing solvent on silica gel plate).
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][C:4]([C:7](=[NH:9])[NH2:8])=[CH:3]1.[Cl:10][C:11]([SH:14])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:10][C:11]1[S:14][N:8]=[C:7]([C:4]2[CH:5]=[CH:6][O:2][CH:3]=2)[N:9]=1
Reactant: N=C(N)c1ccoc1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Clc1nc(-c2ccoc2)ns1
Temperature: 25 °C
Yield: 32.3 %

Procedure:
To a solution of furan-3-carboximidamide hydrochloride (2.00 g, 13.6 mmol) and perchloromethyl mercaptan (1.47 ml, 13.6 mmol) in dichloromethane (40 ml) was added dropwise a solution of sodium hydroxide (2.72 g, 68.0 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 0.82 g (32.2%) of the desired product as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:11]C)[C:3]=1[NH:13][C:14](=[O:16])[CH3:15].B(Br)(Br)Br.CO.CCCCCC.CCOC(C)=O>C(Cl)Cl.C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([OH:11])[C:3]=1[NH:13][C:14](=[O:16])[CH3:15]
Reactant: COc1cc([N+](=O)[O-])cc(Br)c1NC(C)=O
Agent: BrB(Br)Br
Solvent: CO
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(=O)Nc1c(O)cc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a slurry of 1.26 g of N-(2-bromo-6-methoxy-4-nitrophenyl)acetamide and 60 mL of methylene chloride at 0° C., 8.7 mL of 1.0 M BBr3 in methylene chloride was added dropwise. The mixture was slowly warmed to rt. and allowed to react overnight. MeOH was added next morning and allowed to stir for 10 min. TLC(50/50 hexane/EtOAc) showed reaction complete, different conditions(90/10 DCM/EtOAc) showed there to be two products. Added satd. NaHCO3, extracted with EtOAc(2×), dried organic over MgSO4 and conc. in vacuo. Recovered 1.16 g of product, NMR(CDCl3 400 MHz) showed the two products to be desired and 4-bromo-2-methyl-6-nitro-benzooxazole. The product was carried on with no fiuther purification.
Reaction SMILES: [CH3:1][C:2]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:3].[C:26]([O:30][C:31]([N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[CH2:42]Cl)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CC#N.CCN(C(C)C)C(C)C>[C:26]([O:30][C:31]([N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[CH2:42][N:10]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[C:2]([CH3:1])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:3])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(NCCCCN1C(=O)c2ccccc2C1=O)c1ccccn1
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)n1c(CN(CCCCN2C(=O)c3ccccc3C2=O)C(C)(C)c2ccccn2)nc2ccccc21

Procedure:
Using General Procedure A: Reaction of 2-[4-(1-methyl-1-pyridin-2-yl-ethylamino)-butyl]-isoindole-1,3-dione in dry CH3CN, N-(tert-butoxycarbonyl)-2-chloromethylbenzimidazole, DIPEA and KI gave 2-{[[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-(1-methyl-1-pyridin-2-yl-ethyl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester as a white foam. 1H NMR (CDCl3) δ 1.18-1.33 (m, 2H), 1.39-1.54 (m, 2H), 1.52 (s, 6H), 1.71 (s, 9H), 2.65 (t, 2H, J=7.5 Hz), 3.43 (t, 2H, J=7.2 Hz), 4.27 (s, 2H), 7.04 (t, 1H, J=4.8 Hz), 7.19-7.31 (m, 3H), 7.55 (td, 1H, J=7.7, 1.7 Hz), 7.62-7.70 (m, 2H), 7.70-7.78 (m, 2H), 7.81 (dd, 1H, J=6.6, 1.6 Hz), 8.06 (d, 1H, J=8.4 Hz), 8.47 (d, 1H, J=3.9 Hz). Deprotection with H2NNH2.H2O using General Procedure E gave a colorless oil. Conversion to the HBr salt gave COMPOUND 222 as a white solid. 1H NMR (D2O) δ 1.36-1.51 (m, 4H), 1.60 (s, 6H), 2.46-2.59 (m, 2H), 2.72-2.84 (m, 2H), 4.56 (s, 2H), 7.54-7.64 (m, 2H), 7.74-7.84 (m, 2H), 8.03 (t, 1H, J=6.6 Hz), 8.21 (d, 1H, J=8.4 Hz), 8.64 (t, 1H, J=7.8 Hz), 8.85 (d, 1H, J=5.4 Hz); 13C NMR (D2O) δ 23.21, 24.88, 26.01, 39.43, 45.77, 53.70, 63.80, 114.23, 125.75, 126.73, 126.84, 131.03, 142.12, 148.73, 153.74, 160.26; ES-MS m/z 338 (M+H). Anal. Calcd. for C20H27N5.3.0HBr.1.4H2O.0.3 C4H10O: C, 40.57; H, 5.75; N, 11.16; Br, 38.19. Found: C, 40.48; H, 5.67; N, 11.01; Br, 38.18.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.Cl>O1CCOCC1>[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:3](=[O:4])[CH2:2][Cl:1])=[CH:9][CH:8]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CCl)Nc1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
3.4 g (30 mol) of 2-chloroacetyl chloride were dissolved in anhydrous dioxane and a solution containing 3.8 g (30 mol) of 4-chloroaniline was added dropwise. After an hour, the batch was poured into ice water, acidified using dilute hydrochloric acid, the supernatant was removed by suction and the residue was washed with water until neutral. The reaction product was recrystallized from ethanol. The yield was 3.2 g.
Reaction SMILES: [CH2:1]([S:8]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[NH:38])SC)=[CH:31][CH:30]=1)=[O:26])[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[C@@H:13]([CH2:15][CH3:16])[CH3:14])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][NH2:40]>ClCCl.CO>[CH2:1]([S:8]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:39][NH2:40])=[NH:38])=[CH:31][CH:30]=1)=[O:26])[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[C@@H:13]([CH2:15][CH3:16])[CH3:14])(=[O:9])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N[C@@H](CCSC)C(=O)NCc1ccc(C(=N)SC)cc1
Reactant: NN
Solvent: CO
Solvent: ClCCl
Product: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N[C@@H](CCSC)C(=O)NCc1ccc(C(=N)NN)cc1
Reaction time: 18 h
Yield: 60.7 %

Procedure:
N-(Benzylsulfonyl)-D-isoleucyl-N1-{4-[imino-(methylthio)methyl]benzyl}-L-methioninamide (49 mg, 0.084 mmol) was dissolved in dichloromethane (2 ml) and methanol (2 ml), to which hydrazine (0.020 ml, 0.624 mmol) was then added and stirred for 18 hours. The solvent was distilled off under reduced pressure and the residue was purified by preparative HPLC to give N-(benzylsulfonyl)-D-isoleucyl-N1-{4-[hydrazino(imino)methyl]benzyl}-L-methioninamide (29 mg, 0.051 mmol; yield 61%).
Reaction SMILES: [C:1](Cl)([NH:3][S:4](Cl)(=[O:6])=[O:5])=O.[CH:9]([NH2:12])([CH3:11])[CH3:10].C(N(CC)CC)C>O1CCCC1>[CH3:1][NH:3][S:4]([NH:12][CH:9]([CH3:11])[CH3:10])(=[O:6])=[O:5]
Reactant: O=C(Cl)NS(=O)(=O)Cl
Reactant: CC(C)N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNS(=O)(=O)NC(C)C
Temperature: 20 °C
Reaction time: 3 h

Procedure:
38.9 parts by weight of methylamidosulfonyl chloride were added a little at a time to a mixture of 17.7 parts of isopropylamine, 33.3 parts of triethylamine and 120 parts of tetrahydrofuran (THF), which was kept at from -70° to -65° C. The mixture was stirred at 20° C. for 3 hours, the insoluble material was filtered off and the solution was evaporated to dryness. The residue on the filter was extracted by stirring with methylene chloride, the mixture was filtered and the solution was concentrated. 30.6 parts of N-methyl-N'-isopropylsulfamide of melting point 50°-52° C. (starting substance) were obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]3[C:14]([C:34]([F:37])([F:36])[F:35])=[N:15][N:16]([C:17]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:18]=4[C:19]([NH:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[O:20])[C:10]=3[C:9]2=[O:38])=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:17]([N:16]2[C:10]3[C:9](=[O:38])[N:8]([C:5]4[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=4)[CH2:13][CH2:12][C:11]=3[C:14]([C:34]([F:36])([F:35])[F:37])=[N:15]2)=[C:18]([CH:28]=1)[C:19]([NH:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:20]
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(I)cc2)CC3)c(C(=O)Nc2cccnc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccccc2)CC3)c(C(=O)Nc2cccnc2)c1
Yield: 94.2 %

Procedure:
2-[6-(4-Iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-N-pyridin-3-yl-benzamide (15 mg, 0.023 mmol) was combined with 5% palladium on carbon and stirred in ethanol under 1 atmosphere of hydrogen for 12 h. The reaction mixture was filtered through diatomaceous earth and the solvent evaporated to give the title compound (11 mg, 95%) as a colorless solid. MS (ES+) 508.0 (M+H)+(100%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][C:5]([CH3:9])=[C:4]([CH3:10])[N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[Cl:8][C:7]1[C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:3][C:4]([CH3:10])=[C:5]([CH3:9])[N:6]=1
Reactant: C1CNCCN1
Reactant: Cc1nc(Cl)c(Cl)nc1C
Product: Cc1nc(Cl)c(N2CCNCC2)nc1C

Procedure:
The title compound was prepared according, to the procedure described in Example 90. Step 1, starting from 2,3-dichloro-5,6-dimethylpyrazine*(0.60 g, 3.39 mmol) and piperazine (0.88 g, 10.2 mmol). Yield 0.51 g (66%). MS m/z 226 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][N:37]([C:40]([CH:42]2[CH2:44][CH2:43]2)=[O:41])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[CH:42]1([C:40]([N:37]2[CH2:38][CH2:39][N:34]([S:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:6]3[CH:5]=[CH:4][C:3]([C:17]4[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=4)=[C:2]([F:1])[CH:7]=3)(=[O:33])=[O:32])[CH2:35][CH2:36]2)=[O:41])[CH2:43][CH2:44]1
Reactant: O=C(C1CC1)N1CCN(S(=O)(=O)c2ccccc2Br)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCN(C(=O)C4CC4)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and (4-((2-bromophenyl)sulfonyl)piperazin-1-yl)(cyclopropyl)-methanone. MS (ESI): mass calcd. for C24H24FN5O3S, 481.16; m/z found, 482.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.63-8.59 (m, 1H), 8.16-8.10 (m, 2H), 8.00 (m, 1H), 7.67-7.62 (m, 1H), 7.58-7.53 (m, 1H), 7.39-7.36 (m, 1H), 7.32-7.30 (m, 1H), 7.28 (s, 1H), 4.76 (s, 2H), 3.48 (s, 4H), 2.94-2.82 (m, 4H), 1.63-1.54 (m, 1H), 0.97-0.89 (m, 2H), 0.79-0.70 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>>[CH3:20][C:18]1[CH:19]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:29]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:30])[C:7]=3[CH2:8]2)[CH3:13])[CH:15]=[N:16][C:17]=1[O:21][CH2:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25]
Reactant: O=COc1ccccc1
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)C(F)F
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1OCC(F)(F)C(F)F
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (310 mg, pale brown solid) from 4-chloro-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (250 mg, 0.60 mmol, Intermediate-18, single enantiomer) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:22]3[C:21](=[O:23])[NH:20][CH:19]=[N:18][C:17]=3[N:16]([CH3:24])[C:15](=[O:25])[C:14]=2[CH3:26])=[C:8]([F:27])[CH:7]=1>>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:22]3[C:21](=[O:23])[N:20]([CH2:2][CH2:3][OH:4])[CH:19]=[N:18][C:17]=3[N:16]([CH3:24])[C:15](=[O:25])[C:14]=2[CH3:26])=[C:8]([F:27])[CH:7]=1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c2c(=O)[nH]cnc2n(C)c1=O
Reactant: OCCBr
Product: Cc1c(Nc2ccc(Br)cc2F)c2c(=O)n(CCO)cnc2n(C)c1=O

Procedure:
The title compound was prepared according to the procedure used for Example 9 by reaction of 2-bromoethanol with compound 9F. 1H NMR (400 MHz, MeOD) δ ppm 1.70 (s, 3H) 3.74 (s, 3H) 3.82 (t, J=5.05 Hz, 2H) 4.13 (t, J=5.05 Hz, 2H) 4.53 (s, 1H) 6.78 (t, J=8.72 Hz, 1H) 7.26 (dd, J=8.21, 1.39 Hz, 1H) 7.37 (dd, J=10.48, 2.15 Hz, 1H) 10.27 (s, 1H) [M+H] calc'd for C17H16BrFN4O3, 424. found, 424.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[N:17][CH:18]=[C:19]([Br:24])[CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:24][C:19]1[CH:20]=[C:21]2[C:16](=[N:17][CH:18]=1)[N:15]=[C:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH:23]=[CH:22]2
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3cc(Br)cnc3n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1cnc2nc(C3CCNCC3)ccc2c1

Procedure:
A solution of bromide 3-4 (3.5 g, 8.92 mmol), CH2Cl2 (20 ml) and TFA (10 ml) was stirred for 1.0 h. The reaction was concentrated and then azeotroped with toluene. The residue was dissolved in 1N NaOH and then extracted with CHCl3. The CHCl3 portion was washed with brine, dried (MgSO4) and concentrated providing amine 3-5 as a brown solid.