Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:9]=[C:8](Cl)[N:7]=1)[CH2:2][CH2:3][CH3:4].C(N(C(C)C)CC)(C)C.[CH2:27]([CH2:29][NH2:30])[OH:28]>CC(N(C)C)=O>[CH2:1]([NH:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:9]=[C:8]([NH:30][CH2:29][CH2:27][OH:28])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nc(Cl)nc(NCCCC)n1
Reactant: NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCCCNc1nc(NCCO)nc(NCCCC)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a 500-ml eggplant-shaped flask were placed 77.8 millimoles of N,N′-dibutyl-6-chloro-[1,3,5]triazine-2,4-diamine, 100 ml of dimethylacetamide, 233.5 millimoles of diisopropylethylamine, and 155.6 millimoles of ethanolamine and the mixture was heated at 160° C. with stirring. After 1.5 hours, the mixture was cooled to room temperature and the solvent was distilled off. A white precipitate in the residue was filtered and the filtrate was purified by silica gel column chromatography to give N,N′-dibutyl-N″-hydroxyethyl-[1,3,5]triazine-2,4,6-triamine.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O.[OH:19][N:20]=[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([OH:24])=[O:23].C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:19][N:20]=[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([OH:24])=[O:23]
Reactant: C1=COCCC1
Reactant: CC(C)CC(=NO)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)CC(=NOC1CCCCO1)C(=O)O
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 87 %

Procedure:
9.6 Milliliters of 3,4-dihydro-2H-pyran and 0.29 g of p-TsOH.H2O were added to 50 ml of a solution of 4.35 g of α-hydroxyimino-isocaproic acid dissolved in dry CH2Cl2. The mixture was stirred for 100 minutes at room temperature. The reaction mixture was added to an aqueous solution saturated with NaHCO3 with ice cooling, and subjected to phase separation. An aqueous solution saturated with NaHCO3 was covered with ethyl acetate, then concentrated hydrochloric acid was added thereto, with stirring under ice cooling, to make the reaction mixture weakly acidic. The ethyl acetate layer was separated, washed with an aqueous selection saturated with NaCl, and dried over magnesium sulfate to obtain 6.00 g (87%) of the title compound as a colorless oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:11][NH2:12])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].C[O:14][C:15](=O)[N:16]=[C:17](SC)[C:18]([C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[CH:34][C:33]=1[F:42])=[N:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[N:9][NH:8][C:7]=1[N:11]1[C:15](=[O:14])[NH:16][C:17]([CH:18]([C:32]2[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[CH:34][C:33]=2[F:42])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[N:30]=[C:29]([CH3:31])[O:28][N:27]=3)=[CH:22][CH:21]=2)=[N:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]nc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)cc1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(-c3noc(C)n3)cc2)c2cc(OC)c(OC)cc2F)[nH]c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.9 %

Procedure:
A solution of 0.140 g of 3-hydrazino-1H-pyrazole-4-carboxylic acid ethyl ester, 0.236 g of [2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example 1d) and 0.209 ml of triethylamine in 6 ml of DMF was heated at 85° C. for 15 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure, the residue was dissolved in 7 ml of methanol, and then 0.251 g of sodium cyanotrihydroborate, 0.086 ml of acetic acid and 0.5 g of MS3A were added and the mixture was stirred at room temperature for 20 hours. Next, 100 ml of ethyl acetate and 50 ml of water were added, and the organic layer was washed with 50 ml of water and 50 ml of saturated brine in that order and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-methanol) to give the title compound (0.152 g) as a light green solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][C:3]=1[F:22].[F:23][C:24]([F:33])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:31][CH2:30][C:28]2[O:27][N:26]=[C:25]([C:24]([F:33])([F:32])[F:23])[N:29]=2)=[O:14])=[CH:4][C:3]=1[F:22]
Reactant: O=C(O)c1cnc(OC2CCC2)c(-c2ccc(Cl)c(F)c2)c1
Reactant: NCc1nc(C(F)(F)F)no1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OC2CCC2)c(-c2ccc(Cl)c(F)c2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-3-fluorophenyl)-6-cyclobutoxy-nicotinic acid (example CB) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 90.1%, 471.1 (M+H)+.
Reaction SMILES: [Cl:1][O-].[Ca+2].Cl[O-].[C:6]([O:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)=[C:12]([Cl:25])[C:11]=1[CH3:26])(=[O:8])[CH3:7]>O.C(O)(=O)C.CC(C)=O>[C:6]([O:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([Cl:1])[CH:19]=2)=[C:12]([Cl:25])[C:11]=1[CH3:26])(=[O:8])[CH3:7]
Reactant: [O-]Cl
Reactant: CC(=O)Oc1cc(Cl)c(Oc2ccc(N)cc2)c(Cl)c1C
Agent: [Ca+2]
Solvent: O
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Oc1cc(Cl)c(Oc2ccc(N)c(Cl)c2)c(Cl)c1C
Temperature: -15 °C
Reaction time: 2 h
Yield: 48.1 %

Procedure:
Calcium hypochlorite (14 mg) was dissolved in a mixture of water (2 mL) and glacial acetic acid (one drop). Methyl[3,5-dichloro-4-(4-aminophenoxy)phenyl] acetate (35 mg) dissolved in acetone (2 mL) was added at −10° C. After stirring at −15° C. for 2 hours, the reaction mixture was concentrated and the residue partioned between sodium hydroxide (1 N) and ethyl acetate. After purification on column (silica gel, ethyl acetate/petrolium ether, 1:4), 17 mg (43%) of methyl[3,5-dichloro-4-(4-amino-3-chlorophenoxy)phenyl] acetate was obtained.
Reaction SMILES: C(O)C.[OH-].[K+].[C:6]1([CH2:12][CH2:13][N:14]2[C:18]([Br:19])=[C:17]([C:20]([O:22]CC)=[O:21])[C:16]([N:25]([CH2:44][CH2:45][CH3:46])[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[NH:43][N:42]=[N:41][N:40]=4)=[CH:29][CH:28]=3)=[N:15]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[C:6]1([CH2:12][CH2:13][N:14]2[C:18]([Br:19])=[C:17]([C:20]([OH:22])=[O:21])[C:16]([N:25]([CH2:44][CH2:45][CH3:46])[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[NH:43][N:42]=[N:41][N:40]=4)=[CH:29][CH:28]=3)=[N:15]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1nn(CCc2ccccc2)c(Br)c1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1nn(CCc2ccccc2)c(Br)c1C(=O)O
Yield: 94.1 %

Procedure:
5 ml of ethanol, 5 ml of water and 226 mg of potassium hydroxide were added to 206 mg of N-[1-(2-phenylethyl)-4-ethoxycarbonyl-5-bromopyrazol-3-yl]-N-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-n-propylamine, and heated under reflux for 5 hours. Ethanol was distilled off under reduced pressure, and 10 ml of water were added to the reaction mixture, which was then made acidic with concentrated hydrochloric acid. The resultant was extracted with 50 ml of dichloromethane. After dried over magnesium sulfate, the extract was concentrated under reduced pressure and dried to obtain 185 mg of the intended compound as a pale yellow, amorphous solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.CC(C)=[O:14].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.O>[Br:1][C:2]1[S:6][C:5]([C:7]([OH:14])=[O:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=Cc1sc(Br)cc1[N+](=O)[O-]
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1sc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
5Bromo-3-nitrothiophene-2-carbaldehyde (0.5953 g, 2.5012 mmol, prepared according to Sone, C; Matsuki, Y Bull Chem Soc Japan, 1963, 36(5), 618-20.) was dissolved in acetone (5 mL) and Jones Reagent (1.5 mL) was added. The reaction was stirred at RT for 1 h. The reaction was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed With water (4×100 mL), dried over MgSO4 filtered and concentrated to give 0.4993 g (1.9892 mmol, 80%) of the product as a light yellow solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Br:25][CH2:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)=[O:28]>CC#N>[Br-:25].[C:19]1([C:12]2([C:10]([O:9][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N+:1]([CH2:26][C:27](=[O:28])[NH:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=5)([CH2:6][CH2:5]4)[CH2:2]3)=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(CBr)Nc1ccccn1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)Nc1ccccn1
Product: [Br-]
Temperature: 25 °C
Yield: 49.2 %

Procedure:
1-Phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (0.79 mmol) and 2-bromo-N-pyridin-2-yl-acetamide (Example 15a) (0.87 mmol) were stirred together in anhydrous MeCN at room temperature for 2.5 days. The reaction mixture was concentrated in vacuo and the yellow solid purified by flash silica gel column chromatography eluting with 2-8% MeOH/dichloromethane to give a tan solid. The solid was dissolved up in refluxing MeCN and the solution was allowed to cool down to room temperature. The resulting crystals were filtered off and washed with a small quantity of cold MeCN to give the title compound (211 mg) as a white crystalline solid.
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.[CH:8]1([C:14]([O:16][CH2:17][CH2:18][O:19][C:20](ON2C(=O)CCC2=O)=[O:21])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([C:14]([O:16][CH2:17][CH2:18][O:19][C:20]([NH:7][C:3]2([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]2)=[O:21])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(OCCOC(=O)C1CCCCC1)ON1C(=O)CCC1=O
Reactant: NC1(C(=O)O)CC1
Product: O=C(NC1(C(=O)O)CC1)OCCOC(=O)C1CCCCC1
Yield: 16.4 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, ACPC (426 mg, 4.2 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl cyclohexanecarboxylate (1.1 g, 3.5 mmol) were reacted to provide 172 mg (16% yield) of the title compound (10) as a white powder after work-up and mass-guided preparative HPLC purification. M.p.: 123.6-125.3° C. 1H NMR (CDCl3, 400 MHz): δ=9.92 (br s, 1H), 6.76 (q, 1H), 6.34 (br s, 0.3H), 5.59 (s, 0.7H), 2.27 (m, 1H), 1.10-1.95 (m, 17H). MS (ESI) nm/z 317.15 (M+NH4)+; 322.13 (M+Na)+; 298.15 (M−H)−.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:35][C@@H:36]([C:38]([NH2:40])=[O:39])[CH3:37]>CC(O)C.O>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:35][C@@H:36]([C:38]([NH2:40])=[O:39])[CH3:37])=[O:5]
Reactant: C[C@@H](N)C(N)=O
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CC(C)O
Solvent: CN1CCOCC1
Product: C[C@@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(N)=O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
A solution of Cbz-Pro-OH (10.1 gm) in 2-propanol (IPA, 100 mL) was cooled to -5° C., and NMM (4.4 mL) was added with additional cooling to -10° C. iso-Butyl chloroformate (5.2 mL) was added dropwise while maintaining the temperature at -10° to -15° C. After the addition was complete, a solution of HCl.D-Ala-NH2 (5.0 gm) and NMM (4.4 mL) in water (50 mL) was added and the mixture was stirred at -10° C. for another 30 minutes. The cooling bath was then removed and the solution stirred another three hours. The reaction was quenched in a mixture of EtOAc (200 mL) and water (100 mL) containing NaHCO3 (5 gm) and NaCl (5 gm). The layers were separated and the aqueous layer extracted with EtOAc (2×100 mL). The organic layers were combined and washed with water (2×50 mL) and then concentrated in vacuo to dryness. The residue was taken up in EtOAc (250 mL) and the solution washed with water (2×50 mL) to remove any residual IPA. The organic solution was concentrated in vacuo to about 50 mL and treated with EtOAc (50 mL) and heptane (50 mL) and the product crystallized. The solids were filtered, washed on the filter with heptane and dried in vacuo to yield 8.2 gm Cbz-Pro-D-Ala-NH2. HPLC: 99.2 pa %, [a]D =-11.2 (CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]([O:19][CH3:20])([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)[CH:4]([OH:6])[CH3:5].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1.O>[CH3:28][S:29]([O:6][CH:4]([CH3:5])[C:3]([O:19][CH3:20])([O:2][CH3:1])[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)(=[O:31])=[O:30]
Reactant: COc1ccc2cc(C(OC)(OC)C(C)O)ccc2c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2cc(C(OC)(OC)C(C)OS(C)(=O)=O)ccc2c1
Temperature: 10 °C

Procedure:
The oil, 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)-propan-2-ol, prepared in Example 15 is dissolved in 200 ml of toluene, cooled to about 10° C., and to that solution is added 10.5 g of triethylamine. Then 8.5 g of methanesulfonyl chloride is added dropwise to the solution and an exothermic reaction is noted along with the precipation of triethylamine hydrochloride crystals. The addition occurs over about a 45 minute period and the solution is allowed to warm to about 20° C. Then the reaction mixture is poured into water and extracted with toluene-ether. The organic extracts are separated, dried over magnesium sulfate and evaporated to yield 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)prop-2-yl methanesulfonate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][NH2:12])=[O:10])=[CH:4][CH:3]=1.[C:13](=S)=[S:14].[OH-].[K+]>O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[O:10][C:13]([SH:14])=[N:12][N:11]=2)=[CH:6][CH:7]=1
Reactant: NNC(=O)Cc1ccc(Cl)cc1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Sc1nnc(Cc2ccc(Cl)cc2)o1
Yield: 45.3 %

Procedure:
A stirred solution of 7.0 grams (0.038 mole) of 4-chlorophenylacetic acid hydrazide, 3.0 grams (0.039 mole) of carbon disulfide and 2.8 grams (0.050 mole) of potassium hydroxide in 10 ml of water and 200 ml of ethanol was heated under reflux for four hours. The ethanol was removed under reduced pressure. The concentrate was taken up in water and the mixture washed with diethyl ether. The aqueous layer was acidified with aqueous 5% hydrochloric acid and then was extracted with diethyl ether. The extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 3.9 grams of 2-(4-chlorophenylmethyl)-5-mercapto-1,3,4-oxadiazole; m.p. 115° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([N:3]1CN(C)C[N:5]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][C:13]=3[N:14]=2)[C:4]1=[O:22])[CH3:2].C(NC(N[C:29]1S[C:31]2[CH:37]=C([N+]([O-])=O)C=C[C:32]=2[N:33]=1)=O)C.C=O.CN.[CH3:45][N:46]1CCOCC1>CO.CCO.O>[C:45]([C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([NH:5][C:4]([NH:3][CH2:1][C:2]3[CH:29]=[N:33][CH:32]=[CH:31][CH:37]=3)=[O:22])[S:11][C:12]=2[CH:18]=1)#[N:46]
Reactant: CCNC(=O)Nc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: CN1CCOCC1
Reactant: CCN1CN(C)CN(c2nc3ccc([N+](=O)[O-])cc3s2)C1=O
Agent: C=O
Agent: CN
Solvent: CCO
Solvent: O
Solvent: CO
Product: N#Cc1ccc2nc(NC(=O)NCc3cccnc3)sc2c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
General procedure for synthesizing 1-ethyl-5-methyl-3-(6-nitro-1,3-benzothiazol-2-yl)-1,3,5-triazinan-2-one: N-Ethyl-N′-(6-nitro-1,3-benzothiazol-2-yl)urea is suspended in an alkanol/water mixture, preferably 1:1 EtOH/H2O at room temperature. A 37% aqueous solution of formaldehyde is added followed by addition of a 2M solution of MeNH2 in MeOH, then about 2 mole equivalents of N-methylmorpholine. The solution is warmed to about 70–85° C., preferably 80° C., then allowed to stir for about 4–24 hours, preferably 4 hours. The slurry is then cooled to room temperature, filtered and washed well with water, dried and the title product is isolated. General Procedure for Grignard Addition:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[C:5](Cl)=[C:4]([Cl:16])[N:3]=1.CCN(C(C)C)C(C)C.ClC1C(NC2C=C(OC(C)C)NN=2)=NC([NH:33][C@H:34]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=2)[CH3:35])=NC=1>CCO>[Cl:16][C:4]1[N:3]=[C:2]([NH:33][C@H:34]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=2)[CH3:35])[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[CH:5]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ncc2Cl)n[nH]1
Reactant: Cc1cc(Nc2nc(Cl)nc(Cl)c2Cl)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc(Nc2cc(Cl)nc(N[C@@H](C)c3ccc(F)cn3)n2)n[nH]1
Temperature: 140 °C
Yield: 26.7 %

Procedure:
To a solution of 2,5,6-trichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 39; 2.0 g, 8.2 mmol) in absolute EtOH (40 ml) were added DIEA (2.5 ml) and (15)-1-(5-fluoropyridin-2-yl)ethanamine (Method 6; 1.2 g, 8.2 mmol) and the resulting solution was heated to 140° C. for 12 hours. The mixture was partitioned between EtOAc and H2O, the organic layer was washed with brine and dried. The solvents were removed under reduced pressure to give an oil which was purified by Gilson (20-75% acetonitrile/H2O, 35 min) to give the titled compound as solid (762 mg). m/z: 383.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3][C:2]=1[C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[Cl-].[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([NH3+:27])[CH:22]=[C:21]2[CH3:28].CCN(C(C)C)C(C)C.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CN(C=O)C>[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([NH:27][C:7]([C:5]1[CH:4]=[N:3][C:2]([C:10]3[N:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[N:1][CH:6]=1)=[O:9])[CH:22]=[C:21]2[CH3:28]
Reactant: O=C(O)c1cnc(-c2ncccn2)nc1
Reactant: Cc1cn([NH3+])c2ccc(F)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cn(NC(=O)c2cnc(-c3ncccn3)nc2)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56 %

Procedure:
A mixture of [2,2′]bipyrimidinyl-5-carboxylic acid (166 mg, 0.82 mmol), 5-fluoro-3-methyl-indol-1-yl-ammonium chloride (164 mg, 0.82 mmol) and DIPEA (106 mg, 0.82 mmol) in DMF (5 mL) is stirred at rt for 5 min. 4-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholin-4-ium chloride (226 mg, 0.82 mmol) is added. The reaction mixture is heated to 50° C. for 1.5 h and then concentrated in vacuo. The residue is taken up in DMSO-d6 and then purified via reverse phase C18 HPLC chromatography eluting with water and acetonitrile containing 0.1% TFA buffer to afford [2,2]bipyrimidinyl-5-carboxylic acid (5-fluoro-3-methyl-indol-1-yl)-amide (56%). MS: 349 (M+H); 1H NMR (300 MHz, CDCl3): δ=2.27 (s, 3H), 7.05 (dt, 1H), 7.33 (s, 1H), 7.36 (dd, 1H), 7.42-7.46 (m, 1H), 7.72 (t, 1H), 9.07 (d, 2H), 9.51 (s, 2H), 12.17 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:25][C:26]2[CH:27]=[C:28]([CH:35]=[CH:36][C:37]=2[Cl:38])[O:29][C@@H:30]([CH3:34])[C:31](O)=[O:32])[C:20]([CH3:39])=[C:19]3[CH3:40])=[O:15])[CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C[N:44](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:44][C:31](=[O:32])[C@@H:30]([O:29][C:28]1[CH:35]=[CH:36][C:37]([Cl:38])=[C:26]([CH:27]=1)[CH2:25][N:21]1[C:22]2[C:18](=[CH:17][C:16]([C:14]([NH:13][C@H:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=3)[CH3:12])=[O:15])=[CH:24][CH:23]=2)[C:19]([CH3:40])=[C:20]1[CH3:39])[CH3:34]
Reactant: Cc1c(C)n(Cc2cc(O[C@@H](C)C(=O)O)ccc2Cl)c2ccc(C(=O)N[C@@H](C)c3ccc(C(C)(C)C)cc3)cc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(C)n(Cc2cc(O[C@@H](C)C(N)=O)ccc2Cl)c2ccc(C(=O)N[C@@H](C)c3ccc(C(C)(C)C)cc3)cc12
Yield: 89.3 %

Procedure:
A solution of (S)-2-(3-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-4-chlorophenoxy)propanoic acid (20 mg, 0.036 mmol), NH4Cl (19 mg, 0.36 mmol), HATU (14 mg, 0.036 mmol) and DIEA (25 μl, 0.144 mmol) in DCM (0.5 ml) was stirred at rt for 1 h. After concentration, the obtained oil was purified by reverse phase prep-HPLC (MeOH/Acetonitrile/water) to afford a white powder (18 mg). ESI-MS (m/z): 560/561/562 [MH]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C([Li])CCC.[CH3:15][O:16][CH2:17]Cl.O>CCOCC.CCCCCC>[CH3:15][O:16][CH2:17][CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2c(c1)CCC2
Reactant: COCCl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: COCC1C=Cc2ccccc21
Reaction time: 0.25 h
Yield: 78 %

Procedure:
To a solution of indane (240 g) in dry ether (1 l) was slowly added, with stirring under a nitrogen atmosphere, 2.2 M solution (1 l) of n-butyllithium in n-hexane at -40° C over an hour. After 15 minutes, to this solution was added chloromethyl methyl ether (170 g) in dry ether (150 ml) under nitrogen at -55° C over 30 minutes. After stirring for another 30 minutes, water (1 l) was added with efficient stirring. The ether layer was separated, the aqueous phase extracted with ether (100 ml) twice, and the combined ether extract was washed with brine and dried over MgSO4. The ether was evaporated and the residual oily substance was distilled to give 1-methoxymethyl indene as yellow oil. (b.p. 50° C/0.2 mmHg, 258 g yield 78%)
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][CH:7]([CH3:20])[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[O-:23][C:24]#[N:25].[K+]>C(O)(=O)C>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][CH:7]([CH3:20])[N:8]([C:24](=[O:23])[NH2:25])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: N#C[O-]
Reactant: CC1Cc2ccc(Br)cc2C(c2ccc([N+](=O)[O-])cc2)=NN1
Agent: [K+]
Solvent: CC(=O)O
Product: CC1Cc2ccc(Br)cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=O
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of 1.80 g (5 mmoles) of 8-bromo-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine in 10 ml of glacial acetic acid is treated with 0.53 g (6.5 mmoles) of potassium cyanate. After 1 hour, the solution is poured onto water, and the precipitated crystals are filtered. The crude product is suspended in 15 ml of hot ethanol. After filtration and drying, 1.56 g (77%) of the title compound are obtained. M.p.: 193°-203° C.