Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(NC(C)C)(C)C.C1C=CC(N[S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:16][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: COc1cc(O)ccc1CN1CCCCC1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COc1cc(OS(=O)(=O)C(F)(F)F)ccc1CN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a stirred solution of 3-methoxy-4-piperidin-1-ylmethylphenol (456 mg, 2.06 mmol) and diisopropylamine (0.77 mL, 4.54 mmol) in DCM (10 mL) at 0° C. was added N-phenyltriflamide (958 mg, 2.68 mmol). After the addition was complete the reaction mixture was allowed to warm to ambient temperature and then stirred overnight. The reaction mixture was concentrated under reduced pressure and then purified by flash chromatography (silica, 40 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as a colourless oil (408 mg, 56%). NMR (CDCl3, 300 MHz): 7.60 (d, J=8.4 Hz, 1H), 6.93 (dd, J=8.4, 2.4 Hz, 1H), 6.80 (d, J=2.4 Hz, 1H), 3.93 (s, 2H), 3.89 (s, 3H), 2.87-2.74 (m, 4H), 1.82-1.75 (m, 4H), 1.57-1.50 (m, 2H).
Reaction SMILES: Cl.O1CCOCC1.[NH2:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:32][C@@H:33]3[CH2:37][CH2:36][CH2:35][N:34]3[C:38](=[O:59])[C:39]([C:57]#[N:58])=[CH:40][C:41]([N:44]3[CH2:49][CH2:48][N:47](C(OC(C)(C)C)=O)[CH2:46][CH2:45]3)([CH3:43])[CH3:42])[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][C:19]=3[F:31])[C:10]=12>C1COCC1>[NH2:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:32][C@@H:33]3[CH2:37][CH2:36][CH2:35][N:34]3[C:38]([C:39](=[CH:40][C:41]([CH3:43])([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[CH3:42])[C:57]#[N:58])=[O:59])[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:20][C:19]=3[F:31])[C:10]=12
Reactant: CC(C)(C)OC(=O)N1CCN(C(C)(C)C=C(C#N)C(=O)N2CCC[C@H]2Cn2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
To a solution of 4N HCl in dioxane (0.5 mL, 0.050 mmol) in THF (1 mL) in the ice bath, was added tert-butyl 4-[4-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-cyano-1,1-dimethyl-4-oxo-but-2-enyl]piperazine-1-carboxylate (32.9 mg, 0.050 mmol). The ice bath was removed, the reaction mixture was stirred for 4 h at room temperature at which point TLC and LC-MS showed the reaction was finished. The mixture was concentrated in vacuo, adjusted with NaHCO3 to pH 6-7, and the aq. layer extracted with CH2Cl2. The combined organic layer was washed by brine, dried over Na2SO4, filtered, and the solvent removed to get product 2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-pyrrolidine-1-carbonyl]-4-methyl-4-piperazin-1-yl-pent-2-enenitrile (24 mg, 0.039 mmol, 85% yield) as an off white powder. LC-MS (ES, m/z): 610 [M+H]
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([N:7]([C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6])C.[OH-].[Na+].C(OCC)C>C1COCC1>[C:15]1([CH3:22])[CH:16]=[C:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[C:14]=1[N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](=[O:6])[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)C(=O)N(c1ccccc1)c1c(C)cc(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(C)c(N(C(=O)C(=O)O)c2ccccc2)c(C)c1
Reaction time: 2 h
Yield: 98.8 %

Procedure:
N-(Mesityl)-oxanilic acid ethyl ester (1.99 g, 8.5 mmol) was dissolved in THF (50 ml), forming a solution. To this solution was added 1M NaOH solution (40 ml), and the mixture was then stirred for 2 hours. Diethyl ether (25 ml) was then added, and the layers were separated. The organic layer was washed with 1 M NaOH solution (40 ml). The aqueous layer was then acidified with 2M HCl until precipitation occurred. The precipitate was then extracted with ethyl acetate (2×50 ml). The ethyl acetate was washed with brine (50 ml), and then dried over MgSO4. Removal of the solvent under reduced pressure provided the product as a white solid (1.74 g, 8.4 mmol, 99% yield). 1H NMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 6.93 (s, 2H), 2.29 (s, 3H), 2.19 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 160.0, 156.1, 138.6, 134.7, 129.5, 128.9, 21.2, 18.5. Anal. Calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C, 63.59; H, 6.32; N, 6.79.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].[CH:27]1(Br)[CH2:31][CH2:30][CH2:29][CH2:28]1.O>CN(C=O)C>[CH:27]1([N:13]2[C:14]3=[N:15][CH:16]=[N:17][C:18]([NH2:20])=[C:19]3[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[N:12]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: BrC1CCCC1
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccccc3c1)nn2C1CCCC1
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.42 mmol) was dissolved in DMF (3 mL) and K2CO3 (220 mg, 1.6 mmol) and cyclopentyl bromide (49.5 μL, 0.46 mmol) were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 330.2, found 330.2.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[C:17]([NH:20][C:21]1[CH:22]=[C:23]([NH:27][CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]([OH:31])=[O:30])[CH:24]=[CH:25][CH:26]=1)(=[O:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.[N:48]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[C@@H:50](O)[CH2:49]2>C1COCC1>[N:48]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[C@@H:50]([O:30][C:29](=[O:31])[CH:28]([NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][C:17](=[O:19])[CH3:18])[CH:22]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:49]2
Reactant: CC(=O)Nc1cccc(NC(C(=O)O)c2ccccc2)c1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
PS-DCC (798 mg, 0.10 mmol, loading: 1.25 mmol/g) is suspended in dry THF (10 mL). (3-Acetylamino-phenylamino)-phenyl-acetic acid hydrochloride (I45) (160 mg, 0.50 mmol), HOBT (153 mg, 0.10 mmol), and (R)-quinuclidin-3-ol (190 mg, 1.50 mmol) are added and the mixture is shaken for 16 hours at RT (Conversion complete by UPLC/MS-UV). PS-DCC is filtered off and washed with THF and then with EtOAc. The filtrate is evaporated, the resulting residue is taken up with EtOAc and washed with 5% NaHCO3, water and brine. The organic layer is separated, dried over Na2SO4, filtered and evaporated to afford the title compound as a yellow oil (196 mg, quantitative yield, mixture of diastereoisomers).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:7]([O:13][CH2:14][O:15][CH3:16])[C:6]([O:17][CH3:18])=[C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[C:27]([OH:36])=[C:26]([O:37][CH2:38][O:39][CH3:40])[C:25]=2[O:41][CH3:42])[C:4]=1[O:43][CH2:44][O:45][CH3:46].[CH3:47]O>>[CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:7]([O:13][CH2:14][O:15][CH3:16])[C:6]([O:17][CH3:18])=[C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[C:27]([O:36][CH3:47])=[C:26]([O:37][CH2:38][O:39][CH3:40])[C:25]=2[O:41][CH3:42])[C:4]=1[O:43][CH2:44][O:45][CH3:46]
Reactant: CO
Reactant: CCCCc1c(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)c(O)c(OC)c2OCOC)c(OC)c1OCOC
Product: CCCCc1c(OC)c(OCOC)c(CCCCCc2c(OCOC)c(OC)c(OC)c(OCOC)c2OC)c(OC)c1OCOC
Reaction time: 3 h

Procedure:
1.3 Grams of 1,4-dimethoxy-2,5-bis(methoxymethoxy)-6-butyl-3-{5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)-4-hydroxyphenyl]pentyl}benzene was dissolved in 50 ml of methanol, to this solution was added an excess amount of diazomethane-ether solution was added and the reaction mixture was stirred for 3 hours. The reaction mixture was concentrated to obtain 1.3 g of 1,4-dimethoxy-2,5-bis(methoxymethoxy)-6-butyl-3-{5-[2,4,5-trimethoxy-3,6-bis(methoxymethoxy)phenyl]pentyl}benzene. Colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.O.O.[Sn](Cl)Cl>CCOCC.Cl>[Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCOCC
Solvent: O
Product: Nc1cc(Cl)cnc1Br
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
2-Bromo-5-chloro-3-nitro-pyridine (11.87 g, 50 mmol) was dissolved in 100 mL ether. Tin(II) chloride dihydrate (56.4 g, 0.5 mol) was dissolved in 100 mL of concentrated hydrochloric acid and added drop wise over 15 minutes to the stirring ethereal solution of the nitro compound. The exothermic reaction brought the ether to boiling and it was allowed to evaporate off. After the addition was complete the reaction mixture was placed on a 50° C. oil bath and stirred for 30 minutes to boil of the remaining ether. The flask was then cooled on in an ice bath. The precipitate formed was collected and by filtration and dissolved in 100 mL of water. The pH was adjusted to 9-10 by the addition of concentrated ammonium hydroxide solution and the product was extracted with ethyl acetate (2×100 mL). The organic layer was washed with diluted ammonium hydroxide, water and brine and dried over Na2SO4 and the solvent was evaporated to afford 7.4 g of tan crystalline solid. MS m/z: 208.9 (M+H).
Reaction SMILES: O=[C:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[CH2:3]1.Cl.[NH2:19][OH:20].N1C=CC=CC=1>C(O)C>[OH:20][N:19]=[C:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[CH2:3]1
Reactant: O=C1Cc2ccccc2C=Cc2ccccc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C1Cc2ccccc2C=Cc2ccccc21
Temperature: 25 °C

Procedure:
To a solution of 5-oxo-dibenzo[a,e]cyclooctene (1 g, Example 1, step E) in ethanol (40 ml) was added hydroxylamine hydrochloride (0.316 g) and pyridine (0.404 ml). This mixture was heated to reflux for 8hr, cooled to room temperature and evaporated to dryness. To the residue was added ethyl acetate (100 ml). water (100 ml),then sodium hydroxide (1M) until pH 10. The aqueous layer was extracted with ethyl acetate (200 ml), the combined organic layers were washed with water (100 ml), brine (100 ml) then dried and evaporated to yield the crude product. Recrystallisation from ethyl acetate-hexane gave pure 5-hydroxyimino-dibenzo[a,e]cyclooctene (0.72 g, m.p. 191°-192°C.
Reaction SMILES: [S:1](=[O:4])(=[O:3])=[O:2].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH:7]=[CH:6]1>>[S:1]([C:7]1[C:8]([O:10][C:5](=[O:11])[CH:6]=1)=[O:9])([OH:4])(=[O:3])=[O:2]
Reactant: O=S(=O)=O
Reactant: O=C1C=CC(=O)O1
Product: O=C1C=C(S(=O)(=O)O)C(=O)O1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
The reagent was prepared using the sulfonation procedure of U.S. Pat. No. 3,987,043 (cited previously). Liquid sulfur trioxide (100 mole %) was added slowly to the agitated maleic anhydride powder while heating to maintain the temperature at 60° C. After the exothermic reaction was complete, the reaction temperature was raised to 100°-110° C. and the mixture was held for 3 hours. After cooling to room temperature, the viscous dark brown oil crystallized to solid sulfomaleic anhydride.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C([O-])(O)=O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(=O)=O>O.C1(C)C=CC=CC=1>[C:16]([N:5]1[CH2:6][C@H:2]([OH:1])[CH2:3][C@@H:4]1[C:7]([OH:9])=[O:8])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)[C@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 96 %

Procedure:
Cis-4-hydroxy-D-proline 8 (10.0 g, 76.3 mmol) was dissolved in H2O (165 mL) containing NaHCO3 (16.0 g, 190 mmol). Benzyl chloroformate (12.5 mL, 15.0 g, 87.7 mmol) in toluene (40 mL) was added to this stirring solution at room temperature over 30 minutes using a dropping funnel. The reaction was stirred for 16 h. By this time, CO2 evolution had ceased, and the two phases were separated. Excess benzyl chloroformate was removed from the aqueous layer by washing with ether (3×50 mL). The aqueous phase was cooled in an ice bath and acidified to pH2 with concentrated HCl, causing precipitation of the oily product. This oil was extracted from the aqueous layer by repeated washings with ethyl acetate (5×50 mL). Further acidification of the aqueous layer produced no more precipitate, indicating the extraction was complete. The combined organic layers were washed with brine, dried (MgSO4), and concentrated to a colorless viscous oil, which crystallized upon standing at room temperature to provide 19.42 g (96%) of N-CBZ-cis-4-hydroxy-D-proline: mp 110°-111° C. (lit. 19 mp 110.5°-111.5° C.); [α]25d +24.4° (c 1.0, CHCl3) ]lit. 19 [α25D +26.3° (c 1.0, CHCl3)].
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f20) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>C(#N)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:15](=[O:16])[CH2:14][C:13](=[O:17])[CH3:12])[CH:9]=2)[NH:4][N:3]=1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Reactant: C=C1CC(=O)O1
Solvent: CC#N
Product: CC(=O)CC(=O)Nc1ccc2[nH]nc(Cl)c2c1
Temperature: 50 °C
Yield: 82.8 %

Procedure:
The product of Step (b) (0.4 g, 2.4 mmol) was dissolved in acetonitrile (1 ml). In a separate flask, diketene (0.18 ml, 2.4 mmol, stabilized with copper sulfate) was dissolved in acetonitrile (1 ml). The diketene solution was added to the amine suspension in three portions, the reaction mixture was sealed and heated to 50° C. for 18 hours. The solvent was evaporated to dryness and purified by silica gel chromatography eluting with 5% MeOH In CH2Cl2 to afford the title compound, (0.5 g, 83%); MS (ES+) m/e 252 [M+H]+.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.[CH3:22][CH:23]([SH:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=3[N:3]=[C:2]2[S:25][CH:23]([CH3:24])[CH3:22])=[CH:13][CH:14]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: CC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Sc1nc2c(c(=O)[nH]c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 80 °C
Yield: 101.5 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.2 g, 0.54 mmol, intermediate 8) in DMF (5 mL) was added propane-2-thiol (0.2 g, 2.7 mmol) and potassium carbonate (0.38 g, 2.7 mmol). The reaction was heated at 80° C. overnight. The mixture was cooled and partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated to give a crude product (0.2 g) which was used without purification. LCMS retention time 1.015 min; LCMS MH+ 365.
Reaction SMILES: [O:1]=[O+][O-].[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:15]#[N:16])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=C.C(Cl)Cl>>[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:15]#[N:16])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:1]
Reactant: O=[O+][O-]
Reactant: C=Cc1ccc(C2(C#N)CC2)cc1
Solvent: ClCCl
Product: N#CC1(c2ccc(C=O)cc2)CC1
Reaction time: 8 h

Procedure:
Ozone was bubbled through a solution of 1-(4-vinylphenyl)cyclopropanecarbonitrile (1.8 g, 0.011 mol) in methylene chloride (40 mL, 0.6 mol) at −78° C. until a blue color appeared and then nitrogen was bubbled throught the solution for 10 minutes. Methyl sulfide was added and the mixture was stirred overnight. The mixture was washed with water and brine successively, dried, and concentrated to give the desired product.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][CH2:11][CH2:12][NH2:13].CS[C:19]([N:23]([CH3:32])[N:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[N:20][C:21]#[N:22]>>[C:21]([N:20]=[C:19]([N:23]([CH3:32])[N:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:13][CH2:12][CH2:11][CH2:10][O:9][C:8]1[CH:14]=[CH:15][CH:16]=[C:6]([CH:2]2[O:3][CH2:4][CH2:5][O:1]2)[CH:7]=1)#[N:22]
Reactant: CSC(=NC#N)N(C)N=Cc1ccccc1
Reactant: NCCCOc1cccc(C2OCCO2)c1
Product: CN(N=Cc1ccccc1)C(=NC#N)NCCCOc1cccc(C2OCCO2)c1

Procedure:
3-[3-(1,3-Dioxolan-2-yl)phenoxy]propanamine (8.92 g) and N-cyano-1-methyl-2-(phenylmethylene) hydrazinecarboximidothioic acid methyl ester (9.28 g) were heated under water-pump vacuum at 80° for 4 h to yield the title compound, a pale yellow glass (16.03 g). TLC silica; ethyl acetate:cyclohexane 1:1; Rf 0.2 NMR (CDCl3) 2.3-2.2 m (10H); 4.36 s (1H), 5.8-6.1 m (8H); 6.55 s (3H); 7.83 m (2H).
Reaction SMILES: C([N:3](CC)CC)C.[C:8](Cl)(=[O:18])[C:9]1[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:11](Cl)=[O:12]>CN(C1C=CN=CC=1)C.ClCCl.C(OCC)(=O)C>[C:8]1(=[O:18])[NH:3][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of MCH17-1 (520 mg), triethyl amine (0.82 mL) and DMAP (24 mg) in 10 mL dichloromethane at 0° C. was added phthaloyl chloride (0.36 mL). The mixture was stirred overnight at rt, diluted with ethyl acetate and washed with 1N HCl, aq. NaHCO3 and brine. It was dried over anhydrous MgSO4, filtered, concentrated and purified by chromatography eluting with 0% to 50% ethyl acetate in hexane to provide 338 mg of phthalimide protected intermediate which was stirred with 5 mL of trifluoroacetic acid at rt for 40 min. The reaction mixture was evaporated to dryness, the residue was suspended in aq. NaHCO3 and extracted 3× with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated to dryness to obtain 220 mg MCH 17-2.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8])[CH:2]=[CH2:3].[OH-].[Na+].[C:13](Cl)(=[O:15])[CH3:14]>C1(C)C=CC=CC=1>[CH2:1]([N:4]([CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8])[C:13](=[O:15])[CH3:14])[CH:2]=[CH2:3]
Reactant: C=CCNCC(OC)OC
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C=CCN(CC(OC)OC)C(C)=O
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
N-allyl-N-dimethoxyethyl amine (30% aqueous, 48.3 grams, 0.10 mole) was added to a glass reaction vessel fitted with a mechanical agitator. The agitator was started and sodium hydroxide (4.44 grams, 0.11 mole) was dissolved in the aqueous amine. Toluene (50 grams) was added and the mixture cooled to 0° to 5° C. Acetyl chloride (8.24 grams, 0.105 mole) was added over 10 minutes while maintaining the temperature below 5° C. The reaction mixture was stirred for 30 minutes at 5° C., agitation was stopped, and the mixture allowed to phase separate. The aqueous layer was discarded. Toluene was removed from the organic layer by rotary evaporation and 14.8 grams (0.08 mole) of N-allyl-N-dimethoxyethyl acetamide was isolated as confirmed by NMR.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[C:8]2[N:7]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:6]3=[C:5]([CH3:25])[C:4]=2[CH:3]=1.Br[C:27]1[S:28][C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=1>>[F:1][C:2]1[CH:10]=[C:9]([C:27]2[S:28][C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=2)[C:8]2[N:7]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:6]3=[C:5]([CH3:25])[C:4]=2[CH:3]=1
Reactant: FC(F)(F)c1nnc(Br)s1
Reactant: Cc1c2n(c3c(B4OC(C)(C)C(C)(C)O4)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4nnc(C(F)(F)F)s4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (10 mg, 14%), MS (ISP) m/z=371.5 [(M+H)+], mp 227° C., was prepared in accordance with the general method of example 171, step B from 8-fluoro-10-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (Example 171, step A) (68.8 mg, 0.2 mmol) and commercially available 2-bromo-5-trifluoromethyl-1,3,4-thiadiazole (69.9 mg, 0.3 mmol).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:38]([NH:40][CH2:41][C:42]([NH:44][C@H:45]([C:56]([N:58]1[CH2:65][CH2:64][CH2:63][C@H:59]1[C:60]([NH2:62])=[O:61])=[O:57])[C@@H:46]([CH3:55])[O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:43])=[O:39])[CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:26])=[O:22])[C@@H:11]([CH3:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[NH:73]([C:95]([O:97][C:98]([CH3:101])([CH3:100])[CH3:99])=[O:96])[C@H:74]([C:85]([O:87]N1C(=O)CCC1=O)=O)[C@@H:75]([CH3:84])[O:76][CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>>[NH:73]([C:95]([O:97][C:98]([CH3:99])([CH3:100])[CH3:101])=[O:96])[C@H:74]([C:85]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:38]([NH:40][CH2:41][C:42]([NH:44][C@H:45]([C:56]([N:58]1[CH2:65][CH2:64][CH2:63][C@H:59]1[C:60]([NH2:62])=[O:61])=[O:57])[C@@H:46]([CH3:55])[O:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[O:43])=[O:39])[CH2:29][O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:26])=[O:22])[C@@H:11]([CH3:20])[O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:87])[C@@H:75]([CH3:84])[O:76][CH2:77][C:78]1[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](COCc1ccccc1)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(N)=O)[C@@H](C)OCc1ccccc1
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](COCc1ccccc1)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(N)=O)[C@@H](C)OCc1ccccc1)[C@@H](C)OCc1ccccc1
Yield: 93.6 %

Procedure:
By using 21.00 g of Boc-Asn-Thr(Bzl)-Gly-Ser(Bzl)-Gly-Thr(Bzl)-Pro-NH2 and 9.37 g of Boc-Thr(Bzl)-OSu, and the same procedure as in Reference Example 18 was repeated to obtain 23.4 g (yield: 93.6%) of the above-mentioned objective product. Melting point: 110-113° C.