Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:20]=[CH:19][C:14]2[O:15][CH2:16][CH2:17][O:18][C:13]=2[CH:12]=1)([O-])=O.C(O)(=O)C.O>[Fe].C1(C)C=CC=CC=1>[O:15]1[CH2:16][CH2:17][O:18][C:13]2[CH:12]=[C:11]([NH:10][C:5]3[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:20]=[CH:19][C:14]1=2
Reactant: O=[N+]([O-])c1ccccc1Nc1ccc2c(c1)OCCO2
Agent: [Fe]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Nc1ccccc1Nc1ccc2c(c1)OCCO2
Yield: 91.5 %

Procedure:
A mixture of 6.3 g (23 mmol) of N-(2-nitrophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-amine, 9.0 g (161 mmol) of iron powder, acetic acid (1 ml), water (35 ml) and toluene (70 ml) were heated to reflux for 8 hours. The reaction mixture was filtered aid to separate the waste. The organic layer of the filtrate was batched off, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 5.1 g (yield: 91%) of N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzene-1,2-diamine) as a brown liquid.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[N+:2]=[N-:3].[C:10]([C:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=1)#[CH:11]>C1(C)C=CC=CC=1>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N:1]2[CH:11]=[C:10]([C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=3)[N:3]=[N:2]2)[CH:5]=1
Reactant: C#CC1=CCN(C(=O)OC(C)(C)C)CC1
Reactant: [N-]=[N+]=Nc1cccnc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(c2cn(-c3cccnc3)nn2)CC1
Yield: 12.4 %

Procedure:
3-Azidopyridine (460 mg) prepared in Example 2 and 620 mg of tert-butyl 4-ethynyl-1,2,3,6-tetrahydropyridine-1-carboxylate were dissolved in 8 ml of toluene and the solution was heated to reflux for 20 hours. The reaction solution was returned to room temperature and the solvent was evaporated in vacuo. The resulting residue was separated and produced by a silica gel chromatography (chloroform/methanol=100/1) to give 121 mg of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:13]([NH2:15])=[O:14].[CH:16](O)=[O:17]>O>[CH2:10]([N:7]1[CH2:8][CH2:9][C:4]2[C:3]([C:13]([NH2:15])=[O:14])=[C:2]([NH:1][CH:16]=[O:17])[S:12][C:5]=2[CH2:6]1)[CH3:11]
Reactant: O=CO
Reactant: CCN1CCc2c(sc(N)c2C(N)=O)C1
Solvent: O
Product: CCN1CCc2c(sc(NC=O)c2C(N)=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of compound F4 (225 mg, 1.00 mmol) in formic acid (5 mL) and water (1 mL) was stirred overnight at room temperature. After that time, the reaction mixture was concentrated under reduced pressure. The residue was mixed with saturated aqueous sodium bicarbonate (50 mL) and extracted with methylene chloride (3×150 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with methanol/methylene chloride (15:85) to afford compound N1 as an off-white solid (208 mg, 82%): 1H NMR (300 MHz, DMSO-d6) δ 11.44 (s, 1H), 8.40 (s, 1H), 7.52 (bs, 1H), 7.03 (bs, 1H), 3.48 (s, 2H), 2.76 (d, J=4.8 Hz, 2H), 2.65 (d, J=4.8 Hz, 2H), 2.54-2.47 (m, 2H), 1.07 (t, J=7.0 Hz, 3H). MS (M+H) 254.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=[CH2:7]>CO.C(OCC)(=O)C.[C].[Pd]>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH2:6][CH3:7])[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: C=Cc1cc(OC)cc(OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1cc(OC)cc(OC)c1
Yield: 84.2 %

Procedure:
3,5-Dimethoxystyrene (8.29 g) is dissolved in a mixture of methanol (70 ml) and ethyl acetate (10 ml), and the mixture is subjected to catalytic hydrogenation with using 10% palladium-carbon (51.4% aqueous, 1.2 g) under atmospheric pressure. One hour thereafter, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; hexane/ethyl acetate) to give 1,3-dimethoxy-5-ethylbenzene (7.07 g).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:30]([O:36][CH2:37][CH3:38])(=[O:35])[CH2:31][C:32]([O-])=[O:33].Cl>O1CCCC1.O.C(OCC)(=O)C>[O:33]=[C:32]([C:14]1[CH:15]=[CH:16][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[CH2:31][C:30]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 180.9 %

Procedure:
To a solution of 3-phenoxybenzoic acid (13.5 g, 63.0 mmol) in tetrahydrofuran (150 ml) was added 1,1′-carbonylbis-1H-imidazole (11.2 g, 69.3 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction solution was added monoethyl malonate magnesium salt (10 g, 34.8 mmol) and the mixture was stirred at room temperature for 2 hrs. To the reaction solution were added ethyl acetate (50 ml) and water (50 ml), and conc. hydrochloric acid was added until the pH of the aqueous layer became acidic. The reaction solution was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-oxo-3-(4-phenoxyphenyl)propionate (17.9 g, 100%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH2:9]2)[CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH2:9]2)[N+:7]=1[O-:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC(c2cccc(Cl)n2)c2cc(C#N)ccc2O1
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(c2cccc(Cl)[n+]2[O-])c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 10 h
Yield: 20.6 %

Procedure:
152 mg of 4-(6-chloro-2-pyridyl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile and 136 mg of m-chloroperbenzoic acid were heated at reflux in 15 ml of chloroform. After 10 hours and 20 hours 80 mg and 50 mg, respectively, of m-chloroperbenzoic acid were added. After 30 hours the mixture was allowed to cool to room temperature, washed in succession with sodium bisulphite solution and sodium bicarbonate solution, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate for the elution to give, after trituration with n-hexane, a solid which was recrystallized from acetonitrile. There were obtained 33 mg of 2-chloro-6-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 195°-196° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.S(Cl)(Cl)=O.[CH3:18][NH:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[NH:26][CH3:27]>ClCCl>[ClH:1].[Cl:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][C:6]([N:19]([CH3:18])[C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[NH:26][CH3:27])=[O:8]
Reactant: O=C(O)COc1c(Cl)cccc1Cl
Reactant: CN[C@@H]1CCCC[C@H]1NC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN[C@@H]1CCCC[C@H]1N(C)C(=O)COc1c(Cl)cccc1Cl
Product: Cl
Yield: 39 %

Procedure:
2,6-dichlorophenoxyacetic acid (0.50 g, 2.3 mmol) was treated with thionyl chloride (6 ml) at room temperature for 60 hours. The solution was concentrated in vacuo to give an oil which was dissolved in dichloromethane (2.5 ml) and added dropwise over three minutes to a stirred solution of trans-(±)-N,N'-dimethylcyclohexane-1,2-diamine (0.35 g, 3.1 mmol) in dichloromethane (2.5 ml). After 1.5 hours at room temperature the mixture was filtered and the filtrate treated with diethyl ether until precipitation occurred. The resulting white solid was recrystallized (dichloromethane-diethyl ether) to give trans-(±)-2-(2,6-dichlorophenoxy)-N-methyl-N-[2-(methylamino)cyclohexyl]acetamide monohydrochloride (171 mg, 19%); VmaxC=0 (liquid file) 1655 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([OH:6])=[O:5].O[Li].O.S(OC)(O[CH3:19])(=O)=O.[NH4+].[Cl-]>C1COCC1>[CH3:19][O:5][C:4](=[O:6])[C:3]1[C:7]([I:11])=[CH:8][CH:9]=[CH:10][C:2]=1[F:1]
Reactant: O=C(O)c1c(F)cccc1I
Reactant: COS(=O)(=O)OC
Agent: [Cl-]
Agent: [Li]O
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(F)cccc1I
Temperature: 50 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a 200 mL round-bottomed flask were added 2-fluoro-6-iodo-benzoic acid (7.5 g, 28.2 mmol), LiOH.H2O (1.42 g, 33.8 mmol), and THF (100 mL). The resulting mixture was warmed to 50° C. and stirred for 2 h. Dimethyl sulfate (4.03 mL, 42.3 mmol) was then added and the mixture was warmed to 65° C. After 2 h, the mixture was cooled to room temperature and NH4Cl(aq) (50 mL, 13 wt % solution) was added. The two resulting layers were thoroughly mixed and then separated. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to a light brown oil (7.79 g, 99% yield). 1H NMR (400 MHz, CDCl3): 7.68-7.60 (m, 1H), 7.15-7.06 (m, 2H), 3.98 (s, 3H).
Reaction SMILES: [CH:1]([F:10])([F:9])[C:2]([F:8])([F:7])[C:3]([F:6])([F:5])[F:4].[Li][C:12]([CH3:15])([CH3:14])C.[CH:16](=[O:23])[C:17]1C=CC=C[CH:18]=1.Cl>CCCCC.CCOCC>[F:7][C:2]([F:8])([C:3]([F:6])([F:5])[F:4])[C:1]([C:14]1[CH:12]=[CH:15][CH:18]=[CH:17][C:16]=1[OH:23])([F:10])[F:9]
Reactant: O=Cc1ccccc1
Reactant: [Li]C(C)(C)C
Reactant: FC(F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: CCCCC
Product: Oc1ccccc1C(F)(F)C(F)(F)C(F)(F)F
Temperature: -80 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
60 ml of ether and 3.6 g (30 mmol) of 1H-heptafluoropropane were placed in a 4-neck flask fitted with anchor stirrer, dropping funnel, and internal thermometer and the mixture was cooled to −80° C. 9 g (20 mmol) of tert-BuLi as a 15% strength solution in pentane were then added dropwise and the mixture was stirred for another 30 minutes at this temperature. 2.1 g (20 mmol) of benzaldehyde in 10 ml of ether were subsequently added dropwise. After stirring at −80° C. for 2 hours, the yellow solution was allowed to come to room temperature and dilute hydrochloric acid was added. The mixture was extracted three times with ether and the combined organic phases were dried and filtered. Purification by distillation gave heptafluoropropylphenyl alcohol in a yield of 70%.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([CH3:14])[C:5]=1[S:15]C(N(C)C)=O.O.Cl>CO>[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:14])[C:5]=1[SH:15]
Reactant: COC(=O)c1ccc(Cl)c(SC(=O)N(C)C)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)ccc(Cl)c1S

Procedure:
6.61 g (purity 85% by weight, 100.1 mmol) of KOH were added to 4.80 g (16.7 mmol) of methyl 4-chloro-3-(dimethylaminocarbonylthio)-2-methylbenzoate in 150 ml of methanol, and the mixture was stirred under reflux for two days. The reaction mixture was freed from solvent, water was added to the residue, which was then acidified with 1M HCl, and the solid was collected by filtration. This gave 3.2 g of pure product.
Reaction SMILES: [C:1]1(C)[C:2](S(O)(=O)=O)=CC=[CH:5][CH:6]=1.[Cl:12][C:13]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=1)(O)[CH2:14][CH2:15][CH3:16].[C:28](=[O:31])(O)[O-:29].[Na+]>O1C=CCCC1>[Cl:12][CH:13]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=1)[CH2:14][CH2:15][CH2:16][O:29][CH:28]1[CH2:5][CH2:6][CH2:1][CH2:2][O:31]1
Reactant: CCCC(O)(Cl)c1ccc(C(C)(C)C)cc1
Reactant: O=C([O-])O
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: C1=COCCC1
Agent: [Na+]
Product: CC(C)(C)c1ccc(C(Cl)CCCOC2CCCCO2)cc1

Procedure:
In 8.7 ml dihydropyran they are added 10 mg p.toluene sulphonic acid (APTS). To this mixture they are added within 30 mn at 60°, 20 g 1-chloro (4-tertbutylphenyl) butanol. After this addition the mixture is still heated at between 60° and 65° C. for 30 mn and kept under stirring for further 90 mn. 0.5 g sodium bicarbonate is thereafter added. The mixture is then stirred for 1 hour. The tetrahydropyranylated derivative is directly used without any further purification.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]([C:20]1[CH:36]=[C:35]2[N:23]([CH2:24][C:25]3[C:26]2=[N:27][C:28]2[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22](=[O:37])[C:21]=1[CH2:38][OH:39])([CH2:18][CH3:19])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C>ClCCl>[C:1]([O:39][CH2:38][C:21]1[C:22](=[O:37])[N:23]2[C:35](=[CH:36][C:20]=1[C:9]([OH:8])([CH2:18][CH3:19])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:26]1=[N:27][C:28]3[C:33]([CH:34]=[C:25]1[CH2:24]2)=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:3])[CH3:2]
Reactant: CCC(O)(CC(=O)OC(C)(C)C)c1cc2n(c(=O)c1CO)Cc1cc3ccccc3nc1-2
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(O)(CC(=O)OC(C)(C)C)c1cc2n(c(=O)c1COC(C)=O)Cc1cc3ccccc3nc1-2
Yield: 69.1 %

Procedure:
Acetic anhydride (70 μl, 0.7 mmol) is added dropwise to a solution of tert-butyl 3-hydroxy-3-[8-(hydroxymethyl)-9-oxo-9,11-dihydroindolizino[1,2-b]quinolin-7-yl]pentanoate (200 mg, 0.46 mmol) and triethylamine (140 μl, 1 mmol) in dichloromethane (5 ml) and the resultant mixture is agitated at ambient temperature for 21 hours. The volatile components are evaporated off and the residue is purified by chromatography on a silica gel column (1-2% MeOH/CH2Cl2), which produces 152 mg of sought compound in the form of a yellow solid, m.p. 195-196° C.
Reaction SMILES: C1(C2NN=C(NC3C(=O)N(C)C=C(C4C=CN=C(N5CCN6C7CCCCC=7C=C6C5=O)C=4CO)C=3)C=2)CC1.C([O-])(=O)C.C([O:47][CH2:48][C:49]1[C:50]([N:81]2[CH2:93][CH2:92][N:84]3[C:85]4[CH2:86][CH2:87][CH2:88][CH2:89][C:90]=4[CH:91]=[C:83]3[C:82]2=[O:94])=[N:51][CH:52]=[CH:53][C:54]=1[C:55]1[CH:60]=[C:59]([NH:61][C:62]2[CH:67]=[CH:66][C:65]([N:68]3[CH2:73][CH2:72][N:71]([CH2:74][C:75]([OH:78])([CH3:77])[CH3:76])[CH2:70][CH2:69]3)=[CH:64][N:63]=2)[C:58](=[O:79])[N:57]([CH3:80])[CH:56]=1)(=O)C.O[Li].O>CC(O)C.C1COCC1.O>[OH:78][C:75]([CH3:77])([CH3:76])[CH2:74][N:71]1[CH2:72][CH2:73][N:68]([C:65]2[CH:66]=[CH:67][C:62]([NH:61][C:59]3[C:58](=[O:79])[N:57]([CH3:80])[CH:56]=[C:55]([C:54]4[CH:53]=[CH:52][N:51]=[C:50]([N:81]5[CH2:93][CH2:92][N:84]6[C:85]7[CH2:86][CH2:87][CH2:88][CH2:89][C:90]=7[CH:91]=[C:83]6[C:82]5=[O:94])[C:49]=4[CH2:48][OH:47])[CH:60]=3)=[N:63][CH:64]=2)[CH2:69][CH2:70]1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(CC(C)(C)O)CC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: CC(=O)[O-]
Agent: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2cc(C3CC3)[nH]n2)c1=O
Agent: [Li]O
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(N3CCN(CC(C)(C)O)CC3)cn2)c1=O
Yield: 41.4 %

Procedure:
Following the procedures as described for the preparation of 118, acetate hydrolysis of 120b (70 mg, 0.1 mmol) with LiOH.H2O in iPrOH/THF (1:1) and H2O, gave 120 (27 mg, 42%) as a gray solid. LCMS: [M+H] 653. 1H NMR (500 MHz, DMSO-d6) δ 8.61 (d, J=3, 1H), 8.50 (d, J=5, 1H), 8.41 (s, 1H), 7.83 (d, J=3, 1H), 7.46 (d, J=2, 1H), 7.36 (m, 2H), 7.24 (d, J=9, 1H), 6.58 (s, 1H), 4.95 (m, 1H), 4.44 (m, 2H), 4.24 (m, 2H), 4.13 (m, 2H), 3.87-3.88 (m, 1H), 3.60 (s, 3H), 3.03-3.05 (m, 4H), 2.64-2.66 (m, 5H), 2.61-2.63 (m, 1H), 2.49-2.51 (m, 2H), 2.24 (s, 2H), 1.70-1.71 (m, 4H), 1.10 (s, 6H).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[H-].[Na+].[CH3:19]I>>[C:10]([N:1]([CH3:19])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Yield: 73 %

Procedure:
Methylation of BocLeuOH (12.5 g.) using sodium hydride and methyl iodide gave BocMeLeuOH in 73% yield. Condensation of BocMeLeuOH (3.7 g.) and HMetNH2 hydrochloride salt (2.8 g.) by the mixed anhydride method using isobutyl chloroformate gave BocMeLeu-MetNH2 in 56% yield. De-t-butoxycarbonylation of BocMeLeu-MetNH2 (3.3 g.) using hydrogen chloride in ethyl acetate gave MeLeu-MetNH2 in 64% yield.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C:5]([NH2:8])([CH3:7])[CH3:6].[C:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:12])[CH3:11].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:9])[C:5]([NH:8][S:19]([C:16]1[CH:15]=[CH:14][C:13]([C:10](=[O:12])[CH3:11])=[CH:18][CH:17]=1)(=[O:21])=[O:20])([CH3:7])[CH3:6]
Reactant: COC(=O)C(C)(C)N
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)NS(=O)(=O)c1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.2 %

Procedure:
methyl-2-amino-2-methylpropanoate hydrochloride (2 g, 13.07 mmol) was dissolved in CH2Cl2 (50 ml), and added with 4-acetylbenzene-1-sulfonyl chloride (2.86 g, 13.07 mmol) and triethylamine (7.2 ml, 52.27 mmol), followed by stirring at room temperature for 12 hours. The resultant solution was added with H2O, extracted with CH2Cl2 (×2), dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed. The resultant mixture was purified with column chromatography so as to obtain methyl-2-(4-acetylphenylsulfonamido)-2-methylpropanoate (2.55 g, 8.52 mmol, 56%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:3]=1.Cl.[CH3:15]O>>[CH3:15][O:12][C:11]([C:7]1[C:5]2[S:6][C:2]([CH3:1])=[CH:3][C:4]=2[CH:10]=[CH:9][CH:8]=1)=[O:13]
Reactant: CO
Reactant: Cc1cc2cccc(C(=O)O)c2s1
Agent: Cl
Product: COC(=O)c1cccc2cc(C)sc12

Procedure:
A solution of 2-methylbenzo[b]thiophene-7-carboxylic acid (5.1 g) in methanol (100 ml) was saturated with hydrogen chloride and then heated under reflux for 18 hours. The solution was evaporated and the residue was dissolved in ether. The ether solution was washed with sodium carbonate solution and dried (Na2SO4). Evaporation of the ether gave 2-methylbenzo[b]thiophene-7-carboxylic acid methyl ester (4.7 g), m.p. 48°-49°.
Reaction SMILES: [CH2:1]([C@H:5]1[C@H:9]([CH2:10][CH2:11][C:12](=[O:18])[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[O:8][C:7](=[O:19])[NH:6]1)[CH:2]([CH3:4])[CH3:3].[CH2:20](O)[CH2:21][OH:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:21]1[O:22][C:7]2([NH:6][C@@H:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C@H:9]([CH2:10][CH2:11][C:12](=[O:18])[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[O:8]2)[O:19][CH2:20]1
Reactant: CC(C)CCC(=O)CC[C@@H]1OC(=O)N[C@H]1CC(C)C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)CCC(=O)CC[C@@H]1OC2(N[C@H]1CC(C)C)OCCO2
Yield: 79 %

Procedure:
A mixture of the product from Example 27 (2.5 g, 9.3 mmol), ethylene glycol (7.5 mL) and p-toluenesulfonic acid (60 mg) in toluene (100 mL) was heated at reflux with a Dean-Stark trap for 8 hours. The cooled mixture was washed with aqueous NaHCO3 and dried over MgSO4. Evaporation of the solvent gave a residue which was flash chromatographed on silica gel eluting with 65/35 hexane-ethyl acetate to give 2.3 g (79%) of product. NMR (300 MHz, CDCl3, ppm): 0.85-0.95 (4d, 12H), 3.5 (m, 1H), 3.95 (s, 4H), 4.15 (m, 1H).
Reaction SMILES: O[CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[C:7](=[O:16])[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1.C1C=CC=CC=1.P(Br)(Br)[Br:26].O>C1(C)C=CC=CC=1>[Br:26][CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[C:7](=[O:16])[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1
Reactant: O=C1Nc2ccccc2Sc2cc(CO)ccc21
Reactant: BrP(Br)Br
Solvent: c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1Nc2ccccc2Sc2cc(CBr)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 4.43 gm. of the alcohol of Step A in 100 cc. of benzene and add 1 cc (10.5 mmole) of phosphorous tribromide. Stir at room temperature for 1 hour, add water and then dilute with toluene. Wash three times with water, dry and strip to a solid residue.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13](O)=[O:14])=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[NH2:25][CH:26]([CH:32]1[CH2:34][CH2:33]1)[C:27]([CH3:31])([CH3:30])[C:28]#[N:29].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:28]([C:27]([CH3:31])([CH3:30])[CH:26]([NH:25][C:13]([C:12]1[C:6]2[C:7](=[N:8][CH:9]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:5]=2)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:21])[CH3:22])[CH:11]=1)=[O:14])[CH:32]1[CH2:34][CH2:33]1)#[N:29]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Reactant: CC(C)(C#N)C(N)C1CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C#N)C(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
In a flask were combined 2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (120 mg, 0.36 mmol), 3-amino-3-cyclopropyl-2,2-dimethyl-propionitrile hydrochloride (75 mg, 0.43 mmol), HOBt (54 mg, 0.40 mmol), and EDC (77 mg, 0.40 mmol). Then added DMF (2 mL) followed by diisopropylethylamine (0.16 mL, 0.90 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (3×) then dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (30% to 50% EtOAc/hexanes) to afford 121 mg (74%) of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-cyano-1-cyclopropyl-2,2-dimethyl-ethyl)-amide as an off-white foam.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].Cl.[CH3:14][O:15][C:16](=[O:26])[CH2:17][C:18]1([CH2:24][NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>ClCCl>[CH3:14][O:15][C:16](=[O:26])[CH2:17][C:18]1([CH2:24][NH:25][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: COC(=O)CC1(CN)CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1(CNC(=O)c2ccccc2[N+](=O)[O-])CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.2 %

Procedure:
To a mixture of 2-nitrobenzoyl chloride (0.3 mL, 2.05 mmol) and (1-aminomethyl-cyclohexyl)-acetic acid methyl ester hydrochloride (500 mg, 2.25 mmol) (prepares according to example A) in dichloromethane (10 mL) is added DIPEA (0.75 mL, 4.02 mmol). The mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated and the resulting residue is purified by flash chromatography with 50% EtOAc in Hexane as the eluent to afford the desired {1-[(2-nitro-benzoylamino)-methyl]-cyclohexyl}-acetic acid methyl ester (680 mg, 99%).
Reaction SMILES: [CH2:1]([C:3]([C:6]1[CH:7]=[CH:8][C:9](F)=[C:10]([CH:13]=1)[CH:11]=O)=[CH:4][CH3:5])[CH3:2].[CH2:15]([O:17][C:18](=[O:21])[CH2:19][SH:20])[CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:15]([O:17][C:18]([C:19]1[S:20][C:9]2[CH:8]=[CH:7][C:6]([C:3]([CH2:1][CH3:2])=[CH:4][CH3:5])=[CH:13][C:10]=2[CH:11]=1)=[O:21])[CH3:16]
Reactant: CC=C(CC)c1ccc(F)c(C=O)c1
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC=C(CC)c1ccc2sc(C(=O)OCC)cc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
A solution of 5-(1-ethyl-propenyl)-2-fluoro-benzaldehyde (8.70 g, 45.3 mmol) in DMF (40 mL) is treated with mercapto-acetic acid ethyl ester (8.16 g, 67.9 mmol) and K2CO3 (12.5 g, 90.6 mmol). The resulting suspension is stirred at 80° C. for 60 min and quenched with water (300 mL). The mixture is extracted with EtOAc (2×200 mL), and the organic layer is dried over Na2SO4, concentrated, and purified using silica gel column chromatography (6% EtOAc/Hex), to give the title compound as an oil (11.0 g, 89%).