Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH:9]1[C:25]2([CH3:26])[CH:12]([CH:13]3[CH:22]([CH2:23][CH2:24]2)[C:21]2([CH3:27])[C:16]([CH2:17][CH:18]([O:28][C:29](=[O:69])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([N:38]4[CH2:42][CH:41]([OH:43])[CH:40]([CH:44]([C:63]5[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=5)[O:45][CH:46]([C:55]5[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=5)[C:47]5[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=5)[CH2:39]4)=[O:37])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[C:70]1(=[O:76])[O:75][C:73](=[O:74])[CH2:72][CH2:71]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:54][O:53][C:50]1[CH:51]=[CH:52][C:47]([CH:46]([C:55]2[CH:56]=[CH:57][C:58]([O:61][CH3:62])=[CH:59][CH:60]=2)[O:45][CH:44]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:40]2[CH2:39][N:38]([C:36](=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:29]([O:28][CH:18]3[CH2:17][C:16]4[C:21]([CH3:27])([CH:22]5[CH:13]([CH2:14][CH:15]=4)[CH:12]4[C:25]([CH3:26])([CH:9]([CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8])[CH2:10][CH2:11]4)[CH2:24][CH2:23]5)[CH2:20][CH2:19]3)=[O:69])[CH2:42][CH:41]2[O:43][C:70](=[O:76])[CH2:71][CH2:72][C:73]([OH:75])=[O:74])=[CH:48][CH:49]=1
Reactant: COc1ccc(C(OC(c2ccccc2)C2CN(C(=O)CCCCCNC(=O)OC3CCC4(C)C(=CCC5C4CCC4(C)C(C(C)CCCC(C)C)CCC54)C3)CC2O)c2ccc(OC)cc2)cc1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(OC(c2ccccc2)C2CN(C(=O)CCCCCNC(=O)OC3CCC4(C)C(=CCC5C4CCC4(C)C(C(C)CCCC(C)C)CCC54)C3)CC2OC(=O)CCC(=O)O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.2 %

Procedure:
Referring to scheme 17, Compound 66(12 g, 12.69 mmol) was mixed with succinic anhydride (1.9 g, 19 mmol) and DMAP (1.56 g, 13 mmol) and dried in a vacuum at 40° C. overnight. The mixture was dissolved in anhydrous dichloromethane (50 mL), triethylamine (2 g, 3.6 mL, 26 mmol) was added and the solution was stirred at room temperature under argon atmosphere for 16 h. It was then diluted with dichloromethane (100 mL) and washed with ice cold aqueous citric acid (5% wt., 100 mL) and water (2×100 mL) The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The crude product was purified by column chromatography to afford compound 68 as white solid (12.1 g, 91% yield; Rf=0.5 in 10% MeOH/CHCl3).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[C:25]([NH:27][S:28]([CH:31]2[CH2:33][CH2:32]2)(=[O:30])=[O:29])=[O:26])[C:5]1=[O:36])[CH:2]=[CH2:3].[C:38](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[C:25]([N:27]([S:28]([CH:31]2[CH2:33][CH2:32]2)(=[O:30])=[O:29])[CH3:38])=[O:26])[C:5]1=[O:36])[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)NS(=O)(=O)C2CC2)C1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)N(C)S(=O)(=O)C2CC2)C1=O
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-N-(cyclopropylsulfonyl)butanamide (8 mg, 0.014 mmol; Example 177, Step B) in DMF (1.0 mL) was added potassium carbonate (2.9 mg, 0.021 mmol) and iodomethane (1.1 μL, 0.017 mmol) at rt. The reaction was stirred for 1 hour. After this time more iodomethane (1.1 μL, 0.017 mmol) and potassium carbonate (2.9 mg, 0.021 mmol) was added and the reaction was stirred at rt for 60 hours. After this time the reaction was partitioned between EtOAc (20 mL) and 1.0 M LiCl (5 mL). The separated organic layer was washed with 1.0 M LiCl (5 mL), dried over MgSO4, filtered and evaporated in vacuo to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10](=[O:23])[NH:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH3:13])=[CH:8][CH:9]=1)=[O:4].CO>[Pd].C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10](=[O:23])[NH:11][CH:12]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH3:13])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)NC(C)c2ccc([N+](=O)[O-])cc2)s1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)NC(C)c2ccc(N)cc2)s1
Reaction time: 3 h

Procedure:
A mixture of 500 mg (1.497 mmol) 5-[1-(4-Nitro-phenyl)-ethylcarbamoyl]-thiophene-2-carboxylic acid methyl ester, 200 mg palladium on charcoal (10%), 10 ml methanol and 5 ml THF was hydrogenated at 30 mbar for 3 h. The catalyst was filtered off, the solvent was evaporated to give 5-[1-(4-amino-phenyl)-ethylcarbamoyl]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][NH:11][CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1.C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([F:29])=[CH:31][CH:32]=3)[CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)N(C)C2CNCC2c2ccc(Cl)cc2)cc1C(F)(F)F
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)c3ccc(F)cc3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide (200 mg, 0.484 mmol) in dichloromethane (2 mL) was added 4-fluorobenzoyl chloride (63 μl, 0.533 mmol) and N,N-diisopropyl ethyl amine (124 μl, 0.727 mmol). The solution was stirred for 3 h at ambient temperature. After diluting with ethyl acetate (15 mL) the solution was washed twice with water (15 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate (15 mL) and dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate=50:50 to 0:100) afforded the title compound (245 mg, 95%) as a light brown oil. MS m/e: 535.2 [M+H]+.
Reaction SMILES: O[C@@H:2]1[CH2:5][C@H:4]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3]1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.[NH2:31][NH2:32]>ClCCl>[NH:31]([C@H:2]1[CH2:5][C@H:4]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3]1)[NH2:32]
Reactant: O=C(N[C@H]1C[C@@H](O)C1)OCc1ccccc1
Reactant: NN
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NN[C@H]1C[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 80 °C

Procedure:
Benzyl (cis-3-hydroxycyclobutyl)carbamate (intermediate 47, 3.26 g, 14.73 mmol) was suspended in a mixture of diisopropylethylamine (4 ml, 23.00 mmol) and dichloromethane (100 mL) and cooled in an acetone/ice bath under nitrogen. Methanesulfonyl chloride (1.3 ml, 16.80 mmol) was added slowly and the solution stirred for minutes. The reaction was partitioned between water (200 mL), saturated ammonium chloride (50 mL) and dichloromethane (100 mL). The aqueous was extracted with additional dichloromethane (100 mL) and the organic layers combined. They were dried with magnesium sulfate and evaporated to dryness under reduced pressure using a 40° C. water bath. The crude solid mesylate was suspended in ethanol (10 mL) and treated with hydrazine (anhydrous, 4 ml, 127 mmol). The slurry was heated at 80° C. As the mixture warmed it became homogeneous. After 2 hours additional hydrazine (2 mL) was added and the flask was fitted with a reflux condenser. The bath temperature was raised to 95° C. After an additional 3 hours the solution was evaporated to dryness under reduced pressure to give benzyl (trans-3-hydrazinylcyclobutyl)carbamate as a thick white oil. It was further dried under high vacuum at 50° C. for 20 minutes then used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[Br:1][C:2]1[CH:9]=[C:8]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(F)cc1Br
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=Cc1ccc(N2CCCCC2)cc1Br
Temperature: 110 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a solution of 2-bromo-4-fluorobenzaldehyde (300 mg, 1.48 mmol) in 3.0 mL of N,N-dimethylformamide was added potassium carbonate (204 mg, 1.48 mmol), piperidine (154 μL, 1.55 mmol) at room temperature. After being stirred at 110° C. overnight, the reaction mixture was diluted with a 2:1 solution of ethyl acetate and hexane. The solution was washed with water, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 75/25) to obtain the title compound (355 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([OH:14])=[N:12][S:11][N:10]=1.[C:15](=[O:26])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.N1C=CC=CC=1.[C:33]([CH2:35][CH2:36][NH:37][CH3:38])#[N:34]>ClCCl.O>[CH3:38][N:37]([C:15]([O:14][C:13]1[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[N:10][S:11][N:12]=1)=[O:26])[CH2:36][CH2:35][C:33]#[N:34]
Reactant: Oc1nsnc1-c1c(Cl)cccc1Cl
Reactant: CNCCC#N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(CCC#N)C(=O)Oc1nsnc1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 290.8 %

Procedure:
In 50 mL of dichloromethane, were dissolved 1.98 g of 3-(2,6-dichlorophenyl)-4-hydroxy-1,2,5-thiadiazole, and 0.8 g of bis(trichloromethyl) carbonate. Thereto, 0.7 g of pyridine was added. The mixture was stirred at room temperature for 12 hours. Thereto, 1.51 g of N-(2-cyanoethyl)-N-methylamine was added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water, and was extracted with dichloromethane. The dichloromethane layer was washed with dilute hydrochloric acid, 10% sodium hydrogencarbonate, and water successively, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 2.8 g of N-(2-cyanoethyl)-N-methyl [3-(2,6-dichlorophenyl)-1,2,5-thiadiazo1-4-yl] carbamate.
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]([NH:15][C@H:16]([C:24]([OH:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])=O)C1C=CC=CC=1.[ClH:27]>CO.CN(C)C=O.[Pd]>[ClH:27].[NH2:11][CH2:12][C:13]([NH:15][C@H:16]([C:24]([OH:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14]
Reactant: O=C(CNC(=O)OCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
23 g of benzyloxycarbonyl-glycyl-phenylalanine are dissolved in 250 ml of a methanol/dimethylformamide mixture (1:1) and submitted to hydrogenation by adding 1 g of palladium/charcoal (5% of Pd) (Pd/C) as the catalyst. The pH is kept constant at 4.5 by adding methanolic hydrochloric acid. After removal of the catalyst, the filtrate is concentrated in vacuo and the residue is precipitated from methanol by adding ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.CCN(CC)CC.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][C:30](Cl)=[O:31]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([N:13]([CH2:14][CH2:15][CH3:16])[C:30](=[O:31])[CH2:29][C:25]1[S:24][CH:28]=[CH:27][CH:26]=1)[CH2:9][CH2:8]2
Reactant: CCCNC1CCc2cccc(OC)c2C1
Reactant: O=C(Cl)Cc1cccs1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCN(C(=O)Cc1cccs1)C1CCc2cccc(OC)c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 60 mg (0.27 mmol) of the free base of N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1) and 0.11 mL Et3N (0.79 mmol) in 5 mL dry CHCl3 was cooled in an ice bath. After adding 0.05 ml (0.41 mmol) 2-thienylacetic acid chloride (A3-1: W=Cl, Cy=2-thienyl) to the mixture the ice bath was removed and the reaction was stirred for 2 hrs at room temperature. In a second step further 0.05 mL (0.41 mmol) of 2-thienylacetic acid chloride (A3-1) were added and the reaction stirred for 20 hrs. The mixture was washed with a saturated solution of aqueous NaHCO3 for several times and finally extracted with CH2Cl2. The organic layers were dried over MgSO4 and the solvent was evaporated in vacuo. Flash chromatography of the residue on silica gel with a mixture of hexane/ethyl acetate 40/1 gave the product N-(8-methoxytetralin-2-yl)-N-propyl-2-(2-thienyl)acetamide.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21](O)=[O:22])=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH3:34][O:35][C:36](=[O:48])[CH2:37][CH2:38][CH2:39][NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[F:47].CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:34][O:35][C:36](=[O:48])[CH2:37][CH2:38][CH2:39][N:40]([C:21](=[O:22])[C:20]1[CH:24]=[C:25]([Cl:27])[CH:26]=[C:18]([O:17][CH2:16][CH2:15][N:14]([C:12]([O:11][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:13])[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH:19]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[F:47]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: COC(=O)CCCNc1ccccc1F
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (0.600 ml) and DMF (0.01 ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.393 g) in anhydrous dichloromethane (5 ml). The reaction was stirred at room temperature for 1 h then a solution of 4-(2-fluoro-phenylamino)-butyric acid methyl ester (0.422 g) in dichloromethane (1.5 ml), DMAP (0.006 g) and DIPEA (0.522 ml) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was removed and the organic phase washed with 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution, water and dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with ethyl acetate:cyclohexane (4:1 v/v), to give the title compound as a colourless gum (0.287 g).
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:16]1[CH2:32][CH2:31][C:19]2([N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][NH:21][C:20]2=[O:30])[CH2:18][CH2:17]1.Cl.[CH3:34][N:35]([CH2:37][CH2:38][Cl:39])[CH3:36]>CN(C=O)C>[ClH:39].[CH3:34][N:35]([CH3:36])[CH2:37][CH2:38][N:21]1[C:20](=[O:30])[C:19]2([CH2:18][CH2:17][N:16]([CH2:15][CH2:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:4]3[S:3][CH:7]=[CH:6][CH:5]=3)[CH2:32][CH2:31]2)[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22]1
Reactant: CN(C)CCCl
Reactant: O=C1NCN(c2ccccc2)C12CCN(CCc1ccccc1-c1cccs1)CC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCN1CN(c2ccccc2)C2(CCN(CCc3ccccc3-c3cccs3)CC2)C1=O

Procedure:
To a heterogenous mixture of unwashed 60% NaH dispersed in mineral oil (96.5 mg, 2.41 mmol) in DMF (3 mL) was added 8-[2-[2-(2-thienyl)phenyl]ethyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (prepared as in Example 5) (208.8 mg, 0.500 mmol). The mixture was stirred until H2 gas evolution was observed to stop (30 min), then treated with N,N-dimethylaminoethyl chloride hydrochloride (158 mg, 1.10 mmol). The resulting reaction mixture was stirred for an additional 18 h under argon atmosphere. The reaction was quenched with aqueous NH4Cl (50 mL), and the crude product was extracted into CHCl3 (2×40 mL). The organic extracts were washed with H2O (5×50 mL), dried over Na2SO4, filtered and concentrated to a crude oil. The crude oil was washed with hexane (3×50 mL) to remove mineral oil, then purified by Tapered prep TLC (6% MeOH in CHCl3) to yield title compound as a free base. The free base was dissolved in CHCl3 (15 mL) and treated with 1.0 mL of 1N HCl in Et2O. HCL salt was precipitated by addition of Et2O, collected by filtration and dried in the vacuum oven at 60° C. for 18 h to yield the title compound as a white amorphous solid.
Reaction SMILES: Cl.[N:2]1([C:7]([NH2:9])=[NH:8])[CH:6]=[CH:5][CH:4]=[CH:3]1.[C:10]([O:14][C:15](N1CCNCC1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C([N:26](CC)C(C)C)(C)C>CC(O)C>[C:10]([O:14][C:15]([NH:9][C:7]([N:2]1[CH2:6][CH2:5][NH:26][CH2:4][CH2:3]1)=[NH:8])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: N=C(N)n1cccc1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC(=N)N1CCNCC1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
A mixture 1H-pyrrole-1-carboxamidine hydrochloride (4.40 g, 30 mmol), N-tert-butoxycarbonyl piperazine (5.59 g, 30 mmol) and N,N-diisopropylethylamine (6.3 mL, 36 mmol) in 2-propanol (50 mL) was refluxed for 24 h, cooled to room temperature and the solvents were removed under reduced pressure. The residue was suspended in acetonitrile (50 mL) and filtered; the white precipitate was washed with acetonitrile (50 mL) and dried under vacuum to yield N-tert-butoxycarbonyl piperazine-1-carboxamidine (6.20 g).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][C@@H:20]1[C@@H:26]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[C@H:25]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[C@@H:24]([CH2:41][O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[O:23][C:21]1=[O:22]>C(OCC)C.CCCCCC>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][C@@H:20]1[C@@H:26]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[C@H:25]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[C@@H:24]([CH2:41][O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[O:23][C:21]1([OH:22])[CH2:1][P:2]([O:5][CH3:6])([O:3][CH3:4])=[O:7]
Reactant: O=C1O[C@H](COC2CCCCO2)[C@@H](OC2CCCCO2)[C@H](OC2CCCCO2)[C@H]1OC1CCCCO1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COP(=O)(CC1(O)O[C@H](COC2CCCCO2)[C@@H](OC2CCCCO2)[C@H](OC2CCCCO2)[C@H]1OC1CCCCO1)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of dimethyl methylphosphonate (15.3 ml) in ethyl ether (300 ml) was added dropwise with cooling (-70° to -78° C.) in a stream of argon a solution of n-butyllithium in n-hexane (1.6M solution, 84 ml), and the mixture was stirred for 30 minutes. To the solution was added dropwise with cooling at the same temperature a solution of 2,3,4,6-tetra-O-(tetrahydropyranyl)-D-glucono-1,5-lactone (23.1 g) in ethyl ether (80 ml). The mixture was stirred for one hour, then the cooling bath was removed, and then the mixture was allowed to warm to 0° C. with stirring. The reaction solution was added to an ice-cooled mixture of 10%(W/V) ammonium chloride solution (250 ml) and ethyl ether (120 ml). The ethyl ether layer was separated. The aqueous layer was subjected to extraction with ethyl ether. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and dried further under reduced pressure to give 3,4,5,7-tetra-O-(tetrahydropyranyl)-1-deoxy-1-(dimethoxyphosphoryl)-D-gluco-2-heptulopyranose (26.6 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(N(CC)CC)C.[CH3:18][O:19][CH2:20]Cl>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:10][CH2:18][O:19][CH3:20])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: COCCl
Reactant: O=Cc1cccc(Br)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOc1c(Br)cccc1C=O
Reaction time: 0.75 h

Procedure:
To 3-bromo-2-hydroxybenzaldehyde (1.33 g, 6.6 mmol) in CH2Cl2 (10 mL) at 0° C. was added triethylamine (0.81 g, 8 mmol) then chloromethyl methyl ether (0.56 g, 7 mmol). The mixture was stirred for 45 minutes and partitioned between CH2Cl2 and saturated NaHCO3(aq). The crude material was purified by silica gel column chromatography eluting with hexanes and ethyl acetate (5:1) to afford the titled compound.
Reaction SMILES: [Cl:1][C:2]1[N:3](CC2C=CC(OC)=CC=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].C(O)(C(F)(F)F)=O.C(S(O)(=O)=O)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[NH:3][CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: COc1ccc(Cn2cc3c(c2Cl)c(=O)n(C)c(=O)n3CC(C)C)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)[nH]cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
Crude 5-chloro-1-isobutyl-6-(4-methoxybenzyl)-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (2.5 g) is dissolved in 5 mL of methylene chloride containing TFA (2 mL) and TFMSA (1.6 mL). The reaction mixture is stirred at room temperature overnight. After routine workup, the obtained crude product is purified by column chromatography to give 730 mg of product as gray solids. MS (ESI) m/z 256.1 [M+H]+.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[C:13](O)(=O)[CH3:14]>>[CH3:13][C:14]1[N:4]2[C:5]3[C:10]([N:11]=[CH:12][C:3]2=[N:1][N:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: NNc1cnc2ccccc2n1
Reactant: CC(=O)O
Product: Cc1nnc2cnc3ccccc3n12

Procedure:
A 5 g. portion of 2-hydrazinoquinoxaline was stirred at reflux temperature in acetic acid for 3 hours. The reaction mixture was then cooled, and was evaporated to dryness under vacuum. The product was found to melt at 210°-12° C. without purification, and was identified as 1-methyl-s-triazolo[ 4,3-a]quinoxaline by NMR analysis and elemental microanalysis, the results of which follow.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH2:7][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5]
Reactant: OCc1ccccc1
Reactant: CCC(=O)CC(=O)OC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCC(=O)CC(=O)OCc1ccccc1

Procedure:
2.50 g (19.2 mmol) of methyl 3-oxovalerate, 6.23 g (57.6 mmol) of benzyl alcohol and 234 mg (1.92 mmol) of 4-dimethylaminopyridine were heated under reflux in 30 ml of toluene overnight. Ethyl acetate was added to the reaction solution. After washing with 1 N hydrochloric acid, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1) to obtain the title compound.