Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[C:1]([O:5][C:6]([NH:8][NH:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCCCCBr
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)CCCCCNNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 35.2 %

Procedure:
A mixture of 25 g of tert-butoxycarbonyl hydrazine, 37 g of ethyl 6-bromohexanoate, 26 g of potassium carbonate and 40 ml of hexamethylphosphoramide (HMPA) was stirred at room temperature for 3.5 hours. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed and dried, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent; chloroform:ethyl acetate=3:1) to give 16 g of ethyl 6-(N'-tert-butoxycarbonylhydrazino)hexanoate (state: oily product, IR: 3350, 1740, 1720 cm-1).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:14][N:15]([CH3:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20]>C(O)(C)C>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[C:16]([N:15]([CH3:24])[CH3:14])[CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CN(C)c1cccc(CN)c1
Reactant: CSc1ncnc2cc(N)ncc12
Solvent: CC(C)O
Product: CN(C)c1cccc(CNc2ncnc3cc(N)ncc23)c1
Yield: 40 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (236 mg, 1.23 mmol) (described in a previous experimental) and 3-dimethylamino-benzylamine (1.36 g, 9.07 mmol) in isopropanol (5 mL) is stirred under N2 at reflux for 1 h, and the resulting product is chromatographed on silica gel (10-15% EtOH/EtOAc), then on alumina (1% EtOH/CHCl3) to give 7-amino-4-(3-dimethylaminobenzylamino)pyrido[4,3-d]pyrimidine (145 mg, 40%) as a white solid. 1H NMR (DMSO) δ 9.11 (1H, s), 8.79 (1H, t, J=5.9 Hz), 8.26 (1H, s), 7.11 (1H, dd, J=8.0, 7.7 Hz), 6.73 (1H, brs), 6.63 (1H, d, J=7.6 Hz), 6.60 (1H, dd, J=8.1, 2.2 Hz), 6.44 (2H, brs), 6.35 (1H, s), 4.67 (2H, d, J=5.8 Hz), 2.86 (6H, s).
Reaction SMILES: N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:25]I.O[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=1[O:36][S:37]([CH3:40])(=[O:39])=[O:38]>C(Cl)Cl>[I:25][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=1[O:36][S:37]([CH3:40])(=[O:39])=[O:38]
Reactant: Cc1ccc(CO)c(OS(C)(=O)=O)c1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(CI)c(OS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of imidazole (4.5 g, 66.6 mmol) and PPh3 (17.4 g, 66.6 mmol) in DCM (180 mL) is slowly added over a period of 10 min of I2 (16.9 g, 66.6 mmol) and it is stirred at RT for 30 min. Then a solution of methanesulfonic acid 2-hydroxymethyl-5-methylphenyl ester (12.0 g, 55.5 mmol) in DCM (40 mL) is added drop wise and it is stirred at RT for 1 h. The reaction mixture is concentrated to about 70 mL. It is then filtered and washed with DCM. The filtrate is concentrated and purified to give the title compound as a solid.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:21][C:22]([C:24]2[CH:28]=[C:27]([O:29][CH2:30][C:31]([N:33]3[CH2:37][CH2:36][CH2:35][C@H:34]3[C:38](=[O:44])[NH:39][CH:40]3[CH2:43][CH2:42][CH2:41]3)=[O:32])[N:26]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:25]=2)=[O:23])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:52](Cl)[CH2:53]Cl.C(O)C>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:21][C:22]([C:24]2[CH:28]=[C:27]([O:29][CH2:30][C:31]([N:33]3[CH2:37][CH2:36][CH2:35][C@H:34]3[C:38](=[O:44])[NH:39][CH:40]3[CH2:43][CH2:42][CH2:41]3)=[O:32])[N:26]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:25]=2)=[O:23])[CH2:16][CH2:17][C:18]([O:20][CH2:52][CH3:53])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reactant: ClCCCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OCC)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 1.30 g 4-[(S)-4-Carboxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester in 22 ml dichloromethane were added 421 mg EDC, 268 mg DMAP and 541 μl ethanol. After 3 h the reaction mixture was concentrated and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 550 mg MS (ES+): m/e=738.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@H:9]([CH2:13][OH:14])[C:10]([OH:12])=[O:11]>C(O)(=O)C>[C:1]([NH:8][C@H:9]([CH2:13][OH:14])[C:10]([OH:12])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H](CO)C(=O)O
Solvent: CC(=O)O
Product: CC(=O)N[C@H](CO)C(=O)O
Temperature: 32.5 °C
Reaction time: 24 h

Procedure:
Acetic anhydride (23.4 ml) was added to the suspension of (R)-2-amino-3-hydroxypropanoic acid compound of formula-3 (20 grams) in acetic acid (300 ml) and stirred for 24 hours at 30-35° C. After completion of the reaction, acetic acid was removed by distillation followed by co-distillation with tetrahydrofuran. Isopropyl alcohol (60 ml) and methyltertiarybutylether (120 ml) was added to the obtained residue and stirred for 30 minutes. The obtained solid was filtered off and then solvent from the filtrate was distilled off completely under reduced pressure to get the title compound.
Reaction SMILES: F[B-](F)(F)F.C[O+](C)C.[Cl:10][C:11]1[C:12]([CH3:27])=[C:13]([C:18]([N:20]2[CH2:25][CH2:24][NH:23][C:22](=O)[CH2:21]2)=[O:19])[CH:14]=[CH:15][C:16]=1[F:17].[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]([NH:35][NH2:36])=O.C(O)CCC>ClCCl>[Cl:10][C:11]1[C:12]([CH3:27])=[C:13]([C:18]([N:20]2[CH2:25][CH2:24][N:23]3[C:33]([C:29]4[S:28][CH:32]=[CH:31][N:30]=4)=[N:35][N:36]=[C:22]3[CH2:21]2)=[O:19])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: Cc1c(C(=O)N2CCNC(=O)C2)ccc(F)c1Cl
Reactant: NNC(=O)c1nccs1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCCCO
Product: Cc1c(C(=O)N2CCn3c(nnc3-c3nccs3)C2)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
Trimethyloxonium tetrafluoroborate (138 mg, 0.887 mmol) was added under argon to a suspension of 4-[(3-chloro-4-fluoro-2-methylphenyl)carbonyl]-2-piperazinone (I59) (200 mg, 0.739 mmol) in dry dichloromethane (DCM) (3.694 ml). The reaction mixture was stirred at room temperature overnight—cloudy mixture. 1,3-thiazole-2-carbohydrazide (I51) (159 mg, 1.108 mmol) was added and the resulting mixture was stirred at room temperature 2 h—reaction mixture was in solution before that a precipitate had appeared. 1-Butanol (3.69 ml) was added—mixture went into solution—and the reaction mixture was stirred at reflux 2 h. The reaction mixture was cooled down to room temperature and DCM was removed in vacuo. The reaction mixture was heated at reflux for 2 h and left at room temperature overnight. The mixture was diluted with DCM (150 mL) and washed with sat. NaHCO3 (2×25 mL), water (25 mL) and brine (25 mL). The resulting organic layer was dried over MgSO4 and concentrated under reduced pressure. NMR: lots of butanol left. The crude product was dissolved in DCM (150 mL) and washed with water (25 mL, 50 mL) and brine (25 mL). The resulting DCM layer was dried over MgSO4 and concentrated under reduced pressure. The foam residue was triturated with Et2O to afford a yellow solid (143.3 mg). The crude product was purified by MDAP (High pH). The obtained solid was dried at 50° C. under vacuum for 1.5 days. The solid was triturated with hexane to get remove the methanol and dried under vacuum at 50° C. to afford the desired product in 75.36 mg as a cream solid.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C.[H][H]>[Ni]>[CH3:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: [H][H]
Agent: [Ni]
Product: CCCCCCCCCCCCCCCCC
Temperature: 240 °C
Reaction time: 12 h

Procedure:
1000 g of 1-octadecanol (Lorol C18 from Cognis) were initially charged in a stirrable pressure vessel with 10 g of a nickel catalyst (Ni-5249 P from Engelhard; Ni content=63% by weight) and heated to 240° C. Subsequently, over a period of 12 h, hydrogen was added through a sparging tube at a pressure of 20 bar and the reaction gases were simultaneously discharged through a valve in the reactor lid. Thereafter, the product was cooled, discharged and filtered. This reaction product was fractionated in a distillation to give pure heptadecane and then deodorized with nitrogen. This gives a colorless, low-odor product which is liquid at 40° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]([C:21]#[N:22])([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].N.C(OCC)(=O)C>C(O)C>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:7][C:8](=[O:9])[NH:22][CH2:21]1)[CH3:2]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(Cl)c(Cl)c1
Agent: N
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(c2ccc(Cl)c(Cl)c2)CNC(=O)C1
Reaction time: 20 h

Procedure:
Combine Raney nickel (twice washed with water and twice washed with ethanol, 3.6 kg), 3-cyano-3-(3,4-dichlorophenyl)pentanedioic acid diethyl ester (1260 g, 3.51 mol), ethanol (9 L), and an aqueous concentrated ammonia solution (1.6 L) in a 5 gallon autoclave. Hydrogenate at 55 psi. After 20 hours, vent the vessel, purge with nitrogen, and filter. Rinse the solids with ethanol (about 1 L). Evaporate the filtrate in vacuo to give a residue. Combine the residue and ethyl acetate (10 L) and extract twice with water (1 L) and then with brine. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give a residue. Crystallize the residue from ethyl acetate (about 1.8 L) and heptane (about 7.2 L) to give a solid. Collect the solid to give the title compound: mp; 98-99° C.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[CH:18][N:19]=[C:4]2[N:3]=1.CN(C)C=O.[S-2:25].[Na+].[Na+]>C(O)(=O)C>[CH2:15]([N:14]1[C:10]2[N:9]=[CH:8][C:7]3[C:2]([SH:25])=[N:3][C:4]4[N:5]([N:17]=[CH:18][N:19]=4)[C:6]=3[C:11]=2[CH:12]=[N:13]1)[CH3:16]
Reactant: CCn1ncc2c1ncc1c(Cl)nc3ncnn3c12
Reactant: [S-2]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCn1ncc2c1ncc1c(S)nc3ncnn3c12
Reaction time: 1 h

Procedure:
5.6 g. of 5-chloro-8-ethyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine (0.02 mol.) are dissolved in 100 ml. of dimethylformamide. 2 g. of powdered sodium sulfide are added and the mixture is stirred for 1 hour. After this time, the solution is carefully acidified with acetic acid. 8-Ethyl-8H-pyrazolo[3',4':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine-5-thiol precipitates and is filtered off.
Reaction SMILES: [O:1]=[C:2]1[C@@H:5]([NH:6]C(=O)OCC2C=CC=CC=2)[C@@H:4]([CH2:17][N:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]2=[O:24])[NH:3]1>CCO.CO.[Pd]>[NH2:6][C@@H:5]1[C:2](=[O:1])[NH:3][C@@H:4]1[CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=[O:24]
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1Cn1ccccc1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: N[C@@H]1C(=O)N[C@@H]1CN1CCCCC1=O
Reaction time: 3 h

Procedure:
Prepared according to example 7, step 3. A solution of benzyl ((3S,4R)-2-oxo-4-((2-oxopyridin-1(2H)-yl)methyl)azetidin-3-yl)carbamate (157 mg, 0.480 mmol) in EtOH:MeOH (5:1, 4.8 mL) was evaculated and backfilled with argon (2×) followed by addition of Pd on C (10%, 33 mg). The system was evacuated and backfilled with H2 (3×). After 3 h of stirring the mixture was filtered over celite, washing with MeOH and concentrated in vacuo. The crude residue was used as such in following step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[N:3]=1.[CH3:10][Mg]Br>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:10])[N:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C[Mg]Br
Solvent: ClCCl
Product: Cc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a 5-L reactor was added 2,4,6-trichloro-1,3,5-triazine (180 g, 976 mmol) and DCM (180 mL). To the solution cooled at 0° C. in a dry ice bath was added methylmagnesium bromide (390 mL, 1171 mmol) over 30 min while the reaction temperature was kept below rt. After the addition, the reaction mixture was placed in an ice-water bath to keep the internal temperature stable at 20° C. After the mixture was stirred overnight at rt, it was cooled to −20° C. and was slowly quenched with ice water (500 mL) (internal temperature was controlled below 0° C.). The mixture was allowed to warm to rt and was transferred to a separation funnel. The organic layer was washed with water (500 mL), and concentrated to afford 2,4-dichloro-6-methyl-1,3,5-triazine (127 g, 774 mmol, 79% yield) as a solid that was carried to the next step.
Reaction SMILES: Cl.C(N)(=N)C1C=CC=CC=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=3)[CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1>>[C:15]1([C:18]2[N:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([Br:30])=[CH:28][CH:29]=3)[CH:21]=[CH:20][N:19]=2)[CH:14]=[CH:13][CH:12]=[CH:17][CH:16]=1
Reactant: Brc1ccc(-c2ccnc(-c3ccc(Br)cc3)n2)cc1
Agent: Cl
Agent: N=C(N)c1ccccc1
Product: Brc1ccc(-c2ccnc(-c3ccccc3)n2)cc1
Yield: 72 %

Procedure:
Benzamidine hydrochloride (4.7 g, 0.03 mole) and 1-dimethylamino-3-dimethylimonio-1- (4-bromophenyl) -1-propene perchlorate are allowed to react as described above in Example 4 for the preparation of 2,4-Bis (4-bromophenyl) -pyrimidine. After work-up and recrystallization from CHCl3 :ethyl ether (1:3 ), 7.2 g (72%) of a white crystalline solid is obtained which melted at 107°-08° C. IR(KBr) 2925, 1597, 1562, 1540, 1427 cm-1. 1H-NMR: (CDCl3) 8.65 (d, 1H, j=5.3 Hz), 8.55-8.52 (m, 2H), 8.02 (d, 2H, j=8.3 Hz), 7.6 (d, 2H, j=8.8 Hz), 7.5-7.46 (m, 3H), 7.44 (d, 1H, j=5.3 Hz). 13C-NMR (CDCl3): 164.6, 162.5, 157.9, 137.6, 135.7, 132.1, 130.8, 128.6, 128.5, 128.2, 125.6, 114.1. MS m/e: 311 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15].[C:17]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].[OH-].[K+]>C(O)C>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([CH:25]=[CH:15][C:14]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH:10]=[C:11]([CH3:12])[CH3:13])=[CH:7][C:2]=2[OH:1])=[O:16])=[CH:27][CH:28]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(OCC=C(C)C)cc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)=CCOc1ccc(C(=O)C=Cc2ccc(C(C)(C)C)cc2)c(O)c1
Temperature: 40 °C
Reaction time: 19 h
Yield: 53 %

Procedure:
To a solution of 54.4 g of 2'-hydroxy-4'-(3-methyl-2-butenyloxy)acetophenone and 40.0 g of 4-t-butylbenzaldehyde in 1000 ml of ethanol was added 81.2 g of potassium hydroxide, and the mixture was stirred at 40° C. for 19 hours. After neutralization with dilute hydrochloric acid, the resulting precipitate was collected by filtration, washed with water, dried and recrystallized from isopropanol to give 47.6 g of 4-t-butyl-2'-hydroxy-4'-(3-methyl-2-butenyloxy)chalcone as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10]Cl)[C:3]=1[O:12][CH3:13].[C-:14]#[N:15].[K+].O>CS(C)=O>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH2:10][C:14]#[N:15])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)c(OC)c(CCl)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(Br)c(OC)c(CC#N)c1
Reaction time: 2 h
Yield: 76.9 %

Procedure:
A solution of 1-Bromo-3-chloromethyl-2,5-dimethoxy-benzene 53 (7.0 g, 26.4 mmol) and KCN (1.7 g, 26.4 mmol) in DMSO (50 ml) was heated to 75° C. After 2 hr, the reaction was cooled and poured into water. The aqueous layer was extracted with EtOAc and the organic layer was dried and concentrated. The product was purified by column chromatography on silica gel (20% EtOac/Hex) to give 54 as an oil (5.2 g, 77%): 1H NMR (DMSO-d6) δ 7.20 (d, 1 H, J=3.0 Hz), 6.99 (d, 1 H, J=3.0 Hz), 4.00 (s, 2 H), 3.75 (s, 6 H)
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[NH2:15])[C:8]([O:10]C)=[O:9].N.Cl>O.C(OCC)(=O)C>[NH2:1][C:2]1[NH:15][C:14]2[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=2[N:4]=1
Reactant: N#CBr
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1nc2cc(C(=O)O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A solution of cyanogen bromide (5.0 mL, 5 M in acetonitrile, 25 mmol) was added to a mixture of methyl 3,4-diaminobenzoate (3.0 g, 18 mmol) in water (50 mL). The reaction was stirred at room temperature overnight. Aqueous ammonia (20 mL) and ethyl acetate (100 mL) were added to the reaction mixture and the layers were separated. The organics were dried over sodium sulfate, filtered, and concentrated. To the crude residue was added 2 N aqueous hydrochloric acid (18 mL, 36.0 mmol) and the mixture was heated at reflux overnight. The reaction was concentrated to give the title compound (2.90 g, 97%). 1H NMR (400 MHz, DMSO-d6, δ): 8.75 (s, 2H), 7.84 (s, 1H), 7.77 (dd, J=1.2, 8.4 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.[NH2:23][CH2:24][C:25]([S:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH3:29])[CH2:26][CH2:27][OH:28].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH2:31]([S:30][C:25]([CH3:29])([CH2:26][CH2:27][OH:28])[CH2:24][NH:23][C:12]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[N:2]([CH3:1])[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:17])=[O:13])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(CN)(CCO)SCc1ccccc1
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(C(=O)NCC(C)(CCO)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
To a mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (2.00 g), 4-amino-3-(benzylthio)-3-methylbutan-1-ol (1.61 g), 1H-1,2,3-benzotriazol-1-ol (0.96 g) and N,N-dimethylformamide (20 ml) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.37 g) at room temperature, and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (2.10 g, yield 65%) as colorless crystals from a fraction eluted with ethyl acetate. melting point 132-133° C.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH3:26])[N:3]=1.[Na]>CO>[CH2:2]([O:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH3:26])[N:3]=1)[C:10]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(Cn2nc(O)c3ccc([N+](=O)[O-])cc32)c(OC)c1
Agent: [Na]
Solvent: CO
Product: COC(=O)c1ccc(Cn2nc(OCc3ccccc3)c3ccc([N+](=O)[O-])cc32)c(OC)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 120.8 %

Procedure:
Methyl 4-(3-hydroxy-6-nitroindazol-1-ylmethyl)-3-methoxybenzoate (T) (35.7 g.) was added to a mixture of sodium (2.3 g.) and methanol (200 ml.). The mixture was stirred for 18 hours, and evaporated. The residue was dissolved in N,N-dimethylformamide (100 ml.), cooled to 0° C., and benzyl bromide (15.5 ml.) added. After 18 hours at ambient temperature, ethyl acetate and 1N sodium hydroxide solution were added. The precipitate was isolated by filtration, washed with ether, and chromatographed by HPLC on silica gel, eluting with dichloromethane, to give methyl 4-(3-benzyloxy-6-nitroindazol-1-ylmethyl )-3-methoxybenzoate (CC) (27 g., 60%) as a solid; NMR (250 MHz, DMSO-d6): 3.84(s,3H, OMe); 3.86(s,3H, OMe); 5.38(s,2H, NCH2); 5.65(s,2H, OCH2); 6.95(d,1H); 7.36 (m,3H); 7.46(m,5H); 7.86(m,2H); 8.66(s,1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:11][CH3:12])=[N:5][C:6](SC)=[N:7][CH:8]=1)#[N:2].O.[NH2:14][NH2:15]>C(O)C>[C:1]([C:3]1[C:4]([NH:11][CH3:12])=[N:5][C:6]([NH:14][NH2:15])=[N:7][CH:8]=1)#[N:2]
Reactant: CNc1nc(SC)ncc1C#N
Reactant: NN
Solvent: O
Solvent: CCO
Product: CNc1nc(NN)ncc1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5-cyano-4-methylamino-2-methylsulfanyl-pyrimidine (25.86 g) from Example 3 and hydrazine hydrate (52 mL) in ethanol (250 mL) was heated at reflux with stirring for 3 hours. The reaction mixture was cooled to room temperature and the insoluble product was collected by filtration, washed with cold aqueous ethanol (1:1) to give 23 g of the title compound. Crystallization from ethanol afforded an analytically pure sample of 5-cyano-2-hydrazino-4-methylamino-pyrimidine; mp 247-249° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:18](ON1C(=O)CCC1=O)([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19]>O1CCOCC1.O>[C:1]([O:5][C:6](=[O:17])[C@@H:7]([NH:8][C:18]([O:20][CH2:21][CH:22]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=2[C:29]2[C:34]1=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
A solution of -tyrosine t-butyl ester (Bachem, 20.0 g, 84.3 mmol) and FMOC-OSu (Bachem, 24.68 g, 71.2 mmol) was dissolved in 400 mL of dioxane and 400 mL of water. The pH of the resulting solution was adjusted to pH=9 and the solution stirred overnight at room temperature. The reaction mixture was concentrated to ½ volume and treated with concentrated HCl until the pH=5. The resulting solution was extracted with ethyl acetate (5×150 mL), the combined organic extracts were dried with MgSO4 and concentrated. The residue was crystallized from hot heptane/EtOAc. The solid that formed was collected by filtration and air dried to give the title compound (28.5 g, 87%) as a white solid.
Reaction SMILES: [F:1][C:2]([C:11]1[CH:12]=[CH:13][C:14]([O:19][CH3:20])=[C:15]([CH:18]=1)[CH:16]=O)([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].[ClH:21].Cl.FC1C=CC(C(F)(F)F)=CC=1C[NH:27][C@H:28]1[CH2:33][CH2:32][CH2:31][NH:30][C@H:29]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[ClH:21].[ClH:21].[C:34]1([C@H:29]2[C@@H:28]([NH:27][CH2:16][C:15]3[CH:18]=[C:11]([C:2]([F:1])([C:3]([F:6])([F:5])[F:4])[C:7]([F:9])([F:8])[F:10])[CH:12]=[CH:13][C:14]=3[O:19][CH3:20])[CH2:33][CH2:32][CH2:31][NH:30]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1C=O
Reactant: Fc1ccc(C(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: Cl
Product: COc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 1 and Compound 17 in the same manner of Compound 2.