Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](O)(=O)/[C:9](=[C:11](\C=O)/Br)/[Br:10].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)C.C(=O)=O>C(O)C>[Br-:10].[Br:10]/[C:9](=[CH:8]\[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[CH:11]=[NH+:1]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: Nc1ccccc1
Agent: O=C=O
Solvent: CCO
Product: BrC(=C\Nc1ccccc1)/C=[NH+]/c1ccccc1
Product: [Br-]

Procedure:
The procedure as disclosed in the literature (Simonis, H. Ber. Deut. Chem. Ges. 1901, 34, 509; U.S. Pat. No. 6,747,159) is used. 3.54 g of aniline are dissolved in 15 ml of ethanol in a 100 ml beaker. Separately, 5 g of mucobromic acid are dissolved in 15 ml of ethanol in a 100 ml Erlenmeyer flask. This solution is added dropwise to the aniline/ethanol solution, with cooling. The reaction mixture turns immediately yellow, then orange, with development of CO2. At the end of the addition, the mixture is heated in a water bath until its volume is reduced by one half. The resulting solution is cooled with an ice-salt mixture, forming a yellow crystalline precipitate. This solid is collected on a fritted glass filter to afford pure product 5; additional product 5 can be recovered from concentration and recrystallization of the mother liquor.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.[N:24]([CH:27]([CH3:29])[CH3:28])=[C:25]=[O:26].N1C=CC=CC=1>C(=O)([O-])O.[Na+]>[CH:27]([NH:24][C:25]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1)=[O:26])([CH3:29])[CH3:28]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Reactant: CC(C)N=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)NC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Temperature: 80 °C
Reaction time: 23 h
Yield: 61.3 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (19.3 mg, 0.063 mmol), 2-isocyanatopropane (25.3 mg, 0.297 mmol) and pyridine (1.5 mL) was stirred at 80° C. for 23 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by preparative HPLC to give the title compound (15.2 mg, 62%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[CH3:9].N([O-])=[O:11].[Na+]>Cl.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:11])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)cnc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc(O)cnc1Cl
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 33.6 %

Procedure:
2-Chloro-3-methyl-5-nitro-pyridine (2 g, 11.6 mmol) and SnCl2.(H2O)2 (7.86 g, 34.8 mmol) are refluxed in MeOH overnight. After cooled down, the mixture is diluted with ethyl acetate, washed with water, brine, dried over MgSO4, concentrated and purified by column chromatography to afford 6-chloro-5-methyl-pyridin-3-ylamine (1.7 g). To the solution of 6-chloro-5-methyl-pyridin-3-ylamine (1.7 g, 11.6 mmol) in 1N HCl is added the solution of NaNO2 (960 mg, 13.92 mmol) in water (10 ml) slowly at 0° C. After the addition, the solution is stirred for 20 min and then heated to 90° C. for 30 min. The solution is cooled down, quenched with K2CO3, extracted with ether, dried over MgSO4, and purified by column chromatography to afford the titled compound (560 mg) as a yellow solid.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][N:12]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C@H:11]([C:21]([NH2:23])=[O:22])[CH2:10]1)=O)(C)(C)C.[C:24]1([CH:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:31][C:32](O)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(Cl)CCl>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[NH2:8][C@H:9]1[CH2:13][N:12]([CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[C@H:11]([C:21]([NH:23][C:32](=[O:33])[CH2:31][CH:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:22])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(N)=O)N(CC2CCCCC2)C1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: N[C@@H]1C[C@@H](C(=O)NC(=O)CC(c2ccccc2)c2ccccc2)N(CC2CCCCC2)C1
Reaction time: 18 h
Yield: 81.1 %

Procedure:
To a stirred solution of 100 mg (0.31 mmol) of trans-4-(t-Butoxycarbonyl)aminocyclohexylmethyl L-proline amide, 70 mg (0.31 mmol) of 3,3 diphenylpropionic acid, 46 mg (0.34 mmol) of HOBT, and 34 mg (0.34 mmol) of triethylamine in 2 ml of anh. DMF under a nitrogen atmosphere was added 65 mg (0.34 mmol) of EDC. The resulting solution was stirred at room temp. for 18 h. The reaction was diluted with 2× its' volume of aq. 10% citric acid solution, and the mixture extracted 2× with EtOAc. The combined EtOAc extracts were washed with water and brine, and were dried over anh. MgSO4. Filtration and concentration gave crude product as a yellow oil. The product was purified via column chromatography over silica gel with 3:2 EtOAc/CHCL3 to give 109 mg (64%) of product as a clear glass.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][CH2:13][OH:14])[CH:6]=[CH:5]2.[N:15]1[NH:16][C:17](=[O:21])[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1.[Cu]>[OH:14][CH2:13][CH2:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([N:16]1[C:17](=[O:21])[CH:18]=[CH:19][CH:20]=[N:15]1)[CH:11]=[CH:10]2
Reactant: OCCc1ccc2cc(Br)ccc2c1
Reactant: O=c1cccn[nH]1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=c1cccnn1-c1ccc2cc(CCO)ccc2c1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A mixture of the product from Example 31E (500 mg, 1.87 mmol), 2H-pyridazin-3-one (180 mg, 1.87 mmol), copper powder (120 mg, 1.87 mmol), and K2CO3 (775 mg, 5.61 mmol, 3 equiv.) in pyridine (75 mL) was stirred at reflux under a dry nitrogen atmosphere for 20 hr. The reaction mixture was cooled to room temperature then concentrated under reduced pressure. Residual pyridine was removed by repeated evaporation with toluene. The residue was partitioned between ethyl acetate (350 mL) and saturated aqueous Na2CO3 The organic layer was washed twice with aqueous NH4OH, dried (MgSO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (75:25 ethyl acetate/hexane) to provide the title compound (270 mg, 54% yield). 1H NMR (CDCl3, 300 MHz) δ 8.11 (d, J=2 Hz, 1H), 7.97–7.93 (m, 1H), 7.88 (t, J=9 Hz, 2H), 7.75–7.68 (m, 2H), 7.41 (dd, J=2, 12 Hz, 1H), 7.31–7.24 (m, 1H), 7.10 (dd, J=2, 12 Hz, 1H), 3.97 (t, J=6 Hz, 2H), 3.06 (t, J=6 Hz, 2H). MS (DCI-NH3) [M+H]+ at 267, [M+NH4]+ at 284.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7][C@@H:6]1[N:16]1[CH2:20][CH2:19][C@H:18]([NH:21]C(=O)OCC2C=CC=CC=2)[C:17]1=[O:32])(=[O:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[NH2:21][C@H:18]1[CH2:19][CH2:20][N:16]([C@H:6]2[CH2:7][CH2:8][C@@H:9]([NH:11][C:12]([CH3:15])([CH3:13])[CH3:14])[CH2:10][C@H:5]2[NH:4][C:1](=[O:3])[CH3:2])[C:17]1=[O:32]
Reactant: CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
Example 1, Alternative Preparation, Step 8: To a solution of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(tert-butylamino)cyclohexyl)-2 -oxopyrrolidin-3-ylcarbamate (22 mg, 0.05 mmol) in methanol (2 mL) was added Pd(OH)2 (20 mg of 50% wet catalyst). The flask was evacuated and back-filled with hydrogen from a hydrogen balloon. The mixture was stirred at room temperature for 1 h and the catalyst was removed by filtration. The filtrate was concentrated in vacuo to provide N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexyl)acetamide (13 mg, 85%). LC/MS found [M+H]+=311.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.C(N(CC)CC)C.[CH3:30][O:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([NH:38][NH2:39])=O)=[CH:34][CH:33]=1>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:36]([C:35]5[CH:40]=[CH:41][C:32]([O:31][CH3:30])=[CH:33][CH:34]=5)=[N:38][N:39]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: COc1ccc(C(=O)NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nnc(-c3ccc4[nH]nc(-c5ccc(F)cc5)c4c3)[nH]2)cc1
Yield: 36.3 %

Procedure:
The procedure described in example 123 using ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (400 mg, 1.25 mmol), triethylamine (0.5 mL, 3.7 mmol) and 4-methoxybenzhydrazide (415 mg, 2.5 mmol) was used to prepare the title compound (175 mg, 37% yield). 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 8.71 (s, 1H), 8.16 (d, 1H), 8.0–8.1 (m, 4H), 7.75 (d, 1H), 7.45 (t, 2H), 7.1 (d, 2H), 3.88 (s, 3H), ES-MS (m/z) 386 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH:17]([CH2:21][CH2:22][CH3:23])[C:18](O)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C(Cl)(=O)C(Cl)=O.[CH3:30][C:31]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:32]=1[NH2:33].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:13][C:12]([C:9]1[CH:8]=[C:7]([S:16][CH:17]([CH2:21][CH2:22][CH3:23])[C:18]([NH:33][C:32]2[C:34]([CH3:38])=[CH:35][CH:36]=[CH:37][C:31]=2[CH3:30])=[O:19])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:4])[CH3:3])[C:10]=1[OH:11])([CH3:14])[CH3:15]
Reactant: CCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)O
Reactant: Cc1cccc(C)c1N
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)Nc1c(C)cccc1C
Temperature: 10 °C
Reaction time: 12 h

Procedure:
The title compound of Example 11 (2.3 g, 0.0068 mole) was dissolved in benzene and the solution cooled to 10° C. in an ice bath. A solution of oxalyl chloride (1.14 g, 0.009 mole) in benzene (10 ml) was added dropwise over a period of 20 minutes. The ice bath was removed and the solution stirred at room temperature for 12 hours. The benzene was removed, fresh benzene (10 ml) added and the procedure repeated. The residue was taken up in benzene and a solution of 2,6-dimethylaniline (0.84 g, 0.007 mole) in benzene (25 ml) added over a period of 20 minutes, followed by the dropwise addition of a solution of triethylamine (1 ml). The solution was stirred for 4 hours and the benzene removed. The residue was taken up in ethyl ether (100 ml), stirred, and the white solid filtered. The filtrate was stripped and the product purified by chromatography on silica. The product was recrystallized from ethyl acetate/hexane, filtered and dried, m.p. ca. 137°-139.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH2:9].CCN(CC)CC.[C:17](=[S:20])([S-:19])N.Cl[CH2:22][C:23](=O)[CH3:24]>C(=S)=S.CC#N>[NH2:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[N:1]1[C:23]([CH3:24])=[CH:22][S:19][C:17]1=[S:20]
Reactant: CC(=O)CCl
Reactant: Nc1ccc(F)cc1N
Reactant: NC(=S)[S-]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: S=C=S
Product: Cc1csc(=S)n1-c1ccc(F)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 g (79 mmol) of commercially available 1,2-diamino-4-fluorobenzene 1b were suspended in CS2 (500 mL), then NEt3 (2 eq, 22 ml) were added dropwise and the mixture stirred at r.t. for 2 h. The resulting dithiocarbamate salt was then filtered off, washed with Et2O and used without further purifications (24 g, yellow powder, 99%). 24 g (79 mmol) of dithiocarbamate salt were suspended in MeCN (500 mL), then commercially available chloroacetone (1.1 eq, 7.14 mL) was added dropwise and the mixture stirred at r.t. for 12 h. The solvent was then removed and HCl 37% (21 mL) was added under vigorous stirring. After 15 min, water (150 mL) was added and the mixture extracted 3×150 mL of CH2Cl2. The organic layer was washed 3×400 mL of water, dried with MgSO4 and evaporated under reduced pressure. 3-(2-Amino-4-fluorophenyl)-4-methyl-1,3-thiazole-2(3H)-thione 2b was obtained by crystallisation from CH2Cl2 as yellow crystals (12.1 g, 68%). Mp=138° C.; 1H NMR (300 MHz, CDCl3) δ=1.95 (3H, d, J=1.2, CH3), 3.80 (2H, brs, NH2), 6.37 (1H, q, J=1.2, H5), 6.57-6.99 (3H, m, Ar); 13C NMR (75 MHz, CDCl3) δ=15.44, 103.9 (d, J=26), 106.4 (d, J=24), 106.6, 119.3 (d, J=3), 130.0 (d, J=11), 144.6 (d, J=12), 163.8 (d, J=248), 189.2; HRMS m/z C10H10N2FS2 [M+H]+ calcd: 241.0264, found: 241.0262. The structure of 3-(2-amino-4-fluorophenyl)-4-methyl-1,3-thiazole-2(3H)-thione was fully established by X-ray single crystal analysis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.CO[C:16]1[C:20](OC)=[N:19][S:18](=[O:23])[N:17]=1.[CH3:24][NH2:25]>CO.C(O)C>[CH3:24][NH:25][C:16]1[C:20]([NH:12][CH2:11][CH2:10][CH2:9][NH:8][C:5]2[C:4]([CH3:13])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[N:19][S:18](=[O:23])[N:17]=1
Reactant: Cc1cc(Br)cnc1NCCCN
Reactant: CN
Reactant: COC1=NS(=O)N=C1OC
Solvent: CO
Solvent: CCO
Product: CNC1=NS(=O)N=C1NCCCNc1ncc(Br)cc1C
Reaction time: 2 h
Yield: 25 %

Procedure:
3-(5-Bromo-3-methylpyrid-2-ylamino)propylamine (1.0 g) was reacted with 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (0.65 g) in methanol for 6 hours. Methylamine in ethanol (15 ml) was added and stirred for 2 hours. After evaporation the residue was recrystallised from a mixture of acetonitrile and ether and then from ethanol to yield 4-methylamino-3-[3-(5-bromo-3-methylpyrid-2-ylamino)propylamino]-1,2,5-thiadiazole-1-oxide (0.37 g, 25%), m.p. 211°-212° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.Cl.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[N:19][CH:20]=1.CCN(C(C)C)C(C)C.[NH2:39][C:40]1[CH:41]=[CH:42][C:43]([C@H:51]2[CH2:56][CH2:55][C@H:54]([OH:57])[CH2:53][CH2:52]2)=[C:44]2[C:48]=1[C:47](=[O:49])[N:46]([CH3:50])[CH2:45]2.C(O)(C(F)(F)F)=O>C1COCC1>[OH:57][C@H:54]1[CH2:55][CH2:56][C@H:51]([C:43]2[CH:42]=[CH:41][C:40]([NH:39][C:6]3[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:14][C:15]4[CH:16]=[CH:17][C:18]([CH2:21][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[N:19][CH:20]=4)[N:7]=3)=[C:48]3[C:44]=2[CH2:45][N:46]([CH3:50])[C:47]3=[O:49])[CH2:52][CH2:53]1.[OH:57][C@H:54]1[CH2:55][CH2:56][C@H:51]([C:43]2[CH:42]=[CH:41][C:40]([NH:39][C:2]3[N:7]=[C:6]([NH:14][C:15]4[CH:16]=[CH:17][C:18]([CH2:21][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[N:19][CH:20]=4)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=3)=[C:48]3[C:44]=2[CH2:45][N:46]([CH3:50])[C:47]3=[O:49])[CH2:52][CH2:53]1
Reactant: CCOP(=O)(Cc1ccc(N)cn1)OCC
Reactant: CN1Cc2c(c(N)ccc2[C@H]2CC[C@H](O)CC2)C1=O
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(Cc1ccc(Nc2nc(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)ncc2C(F)(F)F)cn1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)cn1)OCC

Procedure:
A solution of 2,4-dichloro-5-trifluoromethylpyrimidine (59 mg, 0.27 mmol), diethyl [(5-aminopyridin-2-yl)methyl]phosphonate hydrochloride (Compound 260A, 76.6 mg, 0.27 mmol), and DIPEA (0.14 mL, 0.82 mmol) in THF (0.5 mL) was stirred at 60° C. for 2 h, after which, the solvents were removed in vacuo. The residue was treated with 7-amino-4-(trans-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (71.1 mg, 0.27 mmol), TFA (0.063 mL, 0.82 mmol, TFE (0.8 mL). The resulting mixture was irradiated in a microwave reactor at 100° C. for 45 min. Solvents were removed in vacuo and the residue was dissolved in DCM (5 mL) and neutralized with sat. NaHCO3 (aq.) (5 mL). The organic phase was separated, aqueous phase extracted with DCM (2×5 mL). The organic phases were combined, dried over MgSO4, filtered, concentrated, and residue was purified by prep TLC (5% 7 N ammonia in MeOH in DCM) to give 1.3 mg of diethyl [(5-{[4-{[7-(trans-4-hydroxycyclohexyl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-pyridin-2-yl)methyl]phosphonate (Example 260) as the more polar spot on TLC (yield: 0.73%) and 3.8 mg of diethyl [(5-{[2-{[7-(trans-4-hydroxycyclohexyl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl]amino}pyridin-2-yl)methyl]phosphonate (Compound 261) as the less polar spot on TLC (yield: 2.1%).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH2:5]([O:7][CH:8]([O:11][CH2:12][CH3:13])[CH2:9][NH2:10])[CH3:6].[CH2:14]1[CH2:18]OC[CH2:15]1>>[CH2:5]([O:7][CH:8]([O:11][CH2:12][CH3:13])[CH2:9][N:10]([CH2:18][C:14]#[CH:15])[CH2:1][C:2]#[CH:3])[CH3:6].[CH2:5]([O:7][CH:8]([O:11][CH2:12][CH3:13])[CH2:9][NH:10][CH2:1][C:2]#[CH:3])[CH3:6]
Reactant: CCOC(CN)OCC
Reactant: C1CCOC1
Reactant: C#CCBr
Product: C#CCN(CC#C)CC(OCC)OCC
Product: C#CCNCC(OCC)OCC

Procedure:
Propargyl bromide (14.7 g of 80% solution in toluene, 0.1 mol) was added to a stirred solution of aminoacetaldehyde diethyl acetal (13.3 g, 0.1 mol) in THF (200 mL). After 2 h the THF was removed and the residual oil was partitioned between ether and sodium hydroxide solution. Evaporation of the ether gave an oil which was chromatographed on silica gel to give 4.7 g of 2,2-diethoxy-N,N-bis-(2-propynyl)ethylamine and 8.1 g of 2,2-diethoxy-N-(2-propynyl)ethylamine.
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.[H-].[Na+].[CH2:23](Br)[CH:24]=[CH2:25]>O1CCCC1>[CH2:25]([O:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1)[CH:24]=[CH2:23]
Reactant: CCOC(=O)c1cc2c(ccn2O)nc1C(=O)OCC
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOn1ccc2nc(C(=O)OCC)c(C(=O)OCC)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Diethyl 1-hydroxypyrrolo[3,2-b]pyridine-5,6-dicarboxylate (6.2 g, 0.022 mol) is dissolved in (200 mL) dry tetrahydrofuran and cooled to 0° C. under nitrogen. Sodium hydride (0.77 g, 0.033 mol) is added in portions over ten minutes and the reaction is stirred for 30 minutes at 0° C. Allyl bromide (2.01 mL, 0.024 mol) is added all at once to the suspension and the mixture allowed to warm to room temperature and then stirred for 16 hours. The mixture is filtered and the filtrate concentrated in vacuo. The resulting oil is chromatographed using 4:1 hexanes/ethyl acetate and then increasing the polarity to 2:1 hexanes/ethyl acetate to give the product as a yellow oil in 89% yield.
Reaction SMILES: [NH:1]([C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61])[C@H:2]([C:27]([N:29]1[CH2:59][CH2:58][CH2:57][C@H:30]1[C:31]([NH:33][C@H:34]([C:42]([NH:44][C@H:45]([C:54]([OH:56])=[O:55])[CH2:46][CH2:47][CH2:48][CH2:49][NH:50][C:51]([CH3:53])=[O:52])=[O:43])[CH2:35][CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])=[O:32])=[O:28])[CH2:3][CH2:4][C:5](=[O:26])[NH:6]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:70][C:71]1[C:76]2[N:77]=[C:78]([C:80]#[N:81])[S:79][C:75]=2[CH:74]=[CH:73][CH:72]=1.C([SiH](C(C)C)C(C)C)(C)C.C(#N)C.C(O)(C(F)(F)F)=O>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:1]([C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61])[C@H:2]([C:27]([N:29]1[CH2:59][CH2:58][CH2:57][C@H:30]1[C:31]([NH:33][C@H:34]([C:42]([NH:44][C@H:45]([C:54]([OH:56])=[O:55])[CH2:46][CH2:47][CH2:48][CH2:49][NH:50][C:51]([CH3:53])=[O:52])=[O:43])[CH2:35][CH2:36][CH2:37][CH2:38][N:39]([CH3:40])[CH3:41])=[O:32])=[O:28])[CH2:3][CH2:4][C:5](=[O:26])[NH2:6].[NH2:70][C:71]1[C:76]2[N:77]=[C:78]([C:80]#[N:81])[S:79][C:75]=2[CH:74]=[CH:73][CH:72]=1
Reactant: CC(=O)NCCCC[C@H](NC(=O)[C@H](CCCCN(C)C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)[SiH](C(C)C)C(C)C
Agent: N#Cc1nc2c(N)cccc2s1
Solvent: CC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCCCC[C@H](NC(=O)[C@H](CCCCN(C)C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 0.08 h

Procedure:
A solution of Cbz-Gln(Trt)ProLys(Me2)Lys(Ac)-aminocyanobenzothiazole (SEQ ID NO:3) (5.26) and triisopropylsilane (4 mL) in TFA/DCM (40 mL, 1/1) was stirred under a N2 atmosphere at −20° C. for 1 hour. After the conversion of starting material to a new species was confirmed by reverse phase HPLC (Agilent 1100 HPLC; column: Phenomonex Synergi, 4 μm 80 Å, 250×4.6 mm. method: 20% ACN to 55% ACN over 15 minutes, 1 mL/min, aqueous buffer contains 0.1% TFA v/v), the reaction mixture was concentrated. The resulting viscous sludge was then flooded with diethyl ether (200 mL), agitated for 5 minutes, and the solids collected via centrifugation and dried under full vacuum to provide crude Cbz-GlnProLys(Me2)Lys(Ac)-aminocyanobenzothiazole (SEQ ID NO:4) (4.4 g).
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:26]([CH3:28])[CH3:27].C(Cl)(Cl)Cl>CN(C=O)C.CO>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:26]([CH3:28])[CH3:27])=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: CC(C)Br
Reactant: Fc1nc(NCc2ccncc2)c2nc[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)n1cnc2c(NCc3ccncc3)nc(F)nc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (2-Fluoro-9H-purin-6-yl)-pyridin-4-ylmethyl-amine (0.6 g, 2.46 mmol) in DMF (10 mL) under an argon atmosphere, at RT, was added K2CO3 (powdered, anhydrous, 1.7 g, 5 eq, 12.3 mmol) followed by 2-bromopropane (2.3 ml, 10 eq, 24.6 mmol). The reaction mixture was stirred at RT for 24 h, when TLC (CHCl3:MeOH; 90:10) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue partitioned between water (200 ml) and EtOAc (50 ml). The aqueous phase was separated and extracted with more EtOAc (2×50 mL). The bulked organic phase was washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo, and the residue was purified by gradient column chromatography on silica gel, eluted with chloroform:methanol (100:0→95:5), to provide the product as a white solid; Yield: 0.40 g (57%). mp 170-173° C. 1H-NMR (d6-DMSO, 250 MHz): δ 1.49 (6 H, d, J 7.5, —CH(CH3)2), 4.63 (3 H, m, —CH(CH3)2+—HNCH2-Pyr), 7.30, 8.47 (4 H, 2×m, Pyr-H), 8.28 (s, 1 H, —N═CH—N—), 8.97 (1 H, s, br, —HNCH2-Pyr). m/z: 287 ([M+H].
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:26][N:25]=1>CN(C=O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:24]3[N:25]=[CH:26][C:27]([C:30]4[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=4)=[CH:28][N:29]=3)=[CH:4][C:3]=2[O:2]1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Reactant: Clc1ccc(-c2cnc(Cl)nc2)cc1
Solvent: CN(C)C=O
Product: Clc1ccc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3c3ccc4c(c3)OCO4)nc2)cc1

Procedure:
Following the same procedure as outlined in Example 12 above, 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (295 mg, 1 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) and 2-chloro-5-(4-chlorophenyl)pyrimidine (113 mg, 0.5 mmol) in DMF (5 mL, anhydrous) were reacted to yield the product as a white solid.