Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[N:16][C:15](S(C)=O)=[N:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O.[NH2:22][NH2:23]>O1CCCC1>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[N:16][C:15]([NH:22][NH2:23])=[N:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(-c2cnc(S(C)=O)nn2)cc1F
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(-c2cnc(NN)nn2)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of methyl 2-fluoro-4-[3-(methylsulfinyl)-1,2,4-triazin-6-yl]benzoate (0.19 g, 0.00064 mol) in tetrahydrofuran (20 mL) was added hydrazine hydrate (63 μL, 0.0013 mol) slowly. The mixture was stirred at RT for 1.5 h. The mixture was concentrated under reduced pressure to yield the desired product. Analytical LCMS: (M+H)+=264.1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:14][C@@H:15]([OH:42])[C@@H:16]([NH:30][C:31](=[O:41])[O:32][C@@H:33]3[C@H:40]4[C@H:36]([O:37][CH2:38][CH2:39]4)[O:35][CH2:34]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:47][N:48]=[C:49]=[O:50].ClCCl>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:14][C@@H:15]([OH:42])[C@@H:16]([NH:30][C:31](=[O:41])[O:32][C@@H:33]3[C@H:40]4[C@H:36]([O:37][CH2:38][CH2:39]4)[O:35][CH2:34]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:49]([NH:48][CH3:47])=[O:50])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCCO)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)OCCCCOc1ccc(C[C@H](NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H](O)CN(CC(C)C)S(=O)(=O)c2ccc3c(c2)OCO3)cc1

Procedure:
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-[4-(4-hydroxybutoxy)benzyl]propylcarbamate was treated with methyl isocyanate/dichloromethane as described earlier to afford the title compound as a solid foam. 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.2 (1H, dd), 1.4 (1H, quintuplet), 1.6-1.8 (4H, m), 1.9-2.0 (1H, m), 2.38 (1H, t), 2.5 (3H, d), 2.7-2.8 (3H, m), 2.9 (1H, d), 2.98 (1H, dd), 3.3-3.4 (1H, m), 3.4-3.5 (1H, m), 3.5-3.6 (3H, m), 3.7 (1H, t), 3.8 (1H, dd), 3.9 (2H, t), 3.95 (2H, t), 4.8 (1H, dt), 5.0 (1H, br s), 5.5 (1H, d), 6.18 (2H, s), 6.78 (2H, d), 6.9 (1H, br s), 7.0-7.1 (3H, m), 7.2 (1H, d), 7.25 (1H, s), 7.3 (1H, d); MS: 744 (M+23); C34H47N3O12S.
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6]([OH:14])=[CH:5][C:3]1=[O:4].[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[CH3:1][N:2]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6]([OH:14])=[C:5]([N+:15]([O-:17])=[O:16])[C:3]1=[O:4]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2c(c1)c(O)cc(=O)n2C
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)c(O)c([N+](=O)[O-])c(=O)n2C
Temperature: 100 °C

Procedure:
To a stirred suspension of 1,6-dimethyl-4-hydroxy carbostyril (1.70g; 0.009 mole) in glacial acetic acid (10 ml) was added concentrated nitric acid (2.5 ml; d, 1.42) with swirling. The solid dissolved on warming to 100° C to give a red solution which precipitated the 3-nitro compound as yellow crystals on cooling. m.p. 185° C. (Found; C, 56.05; H, 4.33; N, 11.86%, C11H10N2O4 requires; C, 56.41; H, 4.30; N, 11.96%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH:6]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7]1.C(N(C(C)C)CC)(C)C.[CH3:25][C:26]1([CH3:39])[C:30]2([CH2:34][S:35](Cl)(=[O:37])=[O:36])[C:31]([CH2:33][CH:27]1[CH2:28][CH2:29]2)=[O:32]>ClCCl>[O:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7][CH:6]1[CH2:5][NH:4][CH2:3][CH2:2][NH:1][S:35]([CH2:34][C@@:30]12[C:26]([CH3:25])([CH3:39])[CH:27]([CH2:28][CH2:29]1)[CH2:33][C:31]2=[O:32])(=[O:37])=[O:36]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)Cl)C(=O)C2
Reactant: NCCNCC1COc2ccccc2O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C2CC[C@]1(CS(=O)(=O)NCCNCC1COc3ccccc3O1)C(=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a solution of 2.1 g (10 mmole) of 2-{N-(2-aminoethyl)]aminomethyl-2,3-dihydrobenzodioxin and 1.3 g (10 mmole) of diisopropylethylamine in 100 ml of dichloromethane stored in an ice bath was added 1.8 g (7.2 mmole) (-)-10-camphorsulfonyl chloride. The mixture was allowed to stir overnight at room temperature. The reaction was next washed with saturated aqueous sodium bicarbonate, with saturated sodium chloride, dried over sodium sulfate, filtered and evaporated in vacuum. Column chromatography on 100 g of silica gel with chloroform as eluant, followed by crystallization from isopropanol gave 1.3 g of the title compound, m.p. 149°-152° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.C([Sn](CCCC)(CCCC)[C:20]([O:22][CH2:23][CH3:24])=[CH2:21])CCC.[F-].[K+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:23]([O:22][C:20]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)=[CH2:21])[CH3:24]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(OCC)c1nc(SC)ncc1C(=O)OCC
Temperature: 25 °C

Procedure:
A solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (10 g, 43.0 mmol), tributyl(1-ethoxyvinyl)stannane (16 ml, 47.3 mmol) and bis(triphenylphosphine)palladium dichloride (1.508 g, 2.149 mmol) in N,N-dimethylformamide (100 mL) was heated to 70° C. for 5 hours. After cooling, the mixture was treated with an aqueous solution of KF (6 g in 12 mL water) and stirred over the weekend at room temperature. The mixture was filtered through diatomaceous earth and washed with ethyl acetate. The filtrate was partitioned between ethyl acetate and brine. The organic phase was washed with brine twice and concentrated. The residue was separated by flash chromatography (0-20% gradient ethyl acetate in hexane) to give the title compound. MS (DCI/NH3) m/z 269 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1.[CH2:23](Br)[CH:24]=[CH2:25].[H-].[Na+]>CN(C)C=O>[CH2:25]([O:8][C:7]1[C:2]([Br:1])=[CH:3][C:4]([F:22])=[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]=[C:10]2[O:20][CH3:21])[CH:6]=1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(-n2c(OC)nc(C(F)(F)F)cc2=O)c(F)cc1Br

Procedure:
using 1-(4-bromo-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone and allyl bromide with sodium hydride in dimethylformamide there is obtained 1-(5-allyloxy-4-bromo-2-fluorophenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone. m.p. 107°-110° C.;
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1.[Li].CCOC(C)=O>C1COCC1>[C:9]([O:8][C:7](=[O:13])[NH:6][C@H:4]1[CH2:5][C@@H:2]([OH:1])[CH2:3]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (3-oxocyclobutyl)carbamate (100 g, 54 mmol) in THF (2000 mL) at −72° C. was added dropwise a solution of lithium trisec-butylhidridoborate (648 mL, 1 M) in THF over 1.5 hrs. The resulting solution was allowed to warm up to rt and stirred for another 1 hr. TLC (petroleum ether: EtOAc=2:1) showed that the starting material was consumed completely. The reaction was quenched with NH4Cl aqueous. Water (1000 mL) and EtOAc (2000 mL) were added to the mixture. The organic layer was separated, dried over MgSO4 and concentrated to give crude material, which was purified by column chromatography with petroleum ether: EtOAc from 10:1 to 1:2 to afford the title compound (62 g, 61% yield) as a white solid.
Reaction SMILES: C([O:4][CH2:5][CH:6]([CH2:20][O:21]C(=O)C)[CH2:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH2:19])=[N:13][C:14]=2Cl)(=O)C.[OH-:25].[Na+]>Cl>[OH:4][CH2:5][CH:6]([CH2:20][OH:21])[CH2:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:25])[NH:13][C:12]([NH2:19])=[N:11][C:10]1=2
Reactant: CC(=O)OCC(CCn1cnc2c(Cl)nc(N)nc21)COC(C)=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Yield: 85 %

Procedure:
A solution of 9-(4-acetoxy-3-acetoxymethyl-but-1-yl)-2-amino-6-chloropurine (15.5 g, 43.6 mmol) in 2M hydrochloric acid (150 ml) was heated under reflux for 2 hours. The solution was then cooled to room temperature and neutralised with 10% sodium hydroxide solution, left to stand at 4° C., and the resulting precipitate filtered off, washed with cold water and recrystallized from water to give 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine as a white crystalline solid (9.4 g, 85%) mp 275-277°.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:13][CH3:14])([CH3:12])[CH2:8]2)=[C:4]([CH3:15])[C:3]=1[CH:16]=O.O.[OH-].[Na+].Cl.[CH3:22][C:23]([CH3:25])=[O:24]>>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:13][CH3:14])([CH3:12])[CH2:8]2)=[C:4]([CH3:15])[C:3]=1[CH:16]=[CH:22][C:23](=[O:24])[CH3:25]
Reactant: CC(C)=O
Reactant: CCC1(C)Cc2c(C)c(Cl)c(C=O)c(C)c2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1(C)Cc2c(C)c(Cl)c(C=CC(C)=O)c(C)c2C1
Yield: 78 %

Procedure:
To a solution of 24.35 g of the 6-chloro-2-ethyl-2,4,7-trimethylindan-5-carboxaldehyde in 73 ml of absolute acetone was added 36 ml of water and 40 g of 2% NaOH. After refluxing for 20 hours, the solution was acidified with 2N HCl and extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 22.08 g of the title compound as brown oil.
Reaction SMILES: [Li][CH2:2]CCC.[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][CH:22]=[CH:23][CH:24]=3)=[C:16]([F:25])[C:15]=2[F:26])=[CH:10][CH:9]=1)[CH3:7].CI.[Cl-].[NH4+].N>C(OCC)C>[CH2:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][C:22]([CH3:2])=[CH:23][CH:24]=3)=[C:16]([F:25])[C:15]=2[F:26])=[CH:12][CH:13]=1)[CH3:7]
Reactant: CCc1ccc(-c2ccc(-c3ccc[se]3)c(F)c2F)cc1
Reactant: [Li]CCCC
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Product: CCc1ccc(-c2ccc(-c3ccc(C)[se]3)c(F)c2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.7 ml (21.7 mmol) of TMP are initially introduced at −15° C. in 10 ml of diethyl ether, and 13.0 ml (20.7 mmol, 15% soln. in hexane) of n-BuLi are metered in. After 30 min, a solution of 6.8 g (19.6 mmol) of 2-(4′-ethyl-2,3-difluorobiphenyl-4-yl)selenophene in 50 ml of diethyl ether is added. When the addition is complete, the batch is warmed to RT and stirred for 90 min. The solution is cooled to −70° C., and 6.0 ml (96.4 mmol) of methyl iodide are added. The reaction mixture is warmed to RT and stirred for 20 h. Sat. ammonium chloride soln. and conc. ammonia soln. are added successively, and the mixture is stirred vigorously for a few minutes. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed successively with water, 2 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane:toluene=9:1). The further purification is carried out by recrystallisation from ethanol and n-heptane. 2-(4′-Ethyl-2,3-difluorobiphenyl-4-yl)-5-methylselenophene is obtained as a solid having an m.p. of 92° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].[C-]#N.[Na+].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[O:7])[CH2:16][CH2:15][C:14]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][C:3]=1[F:10]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: C=CC(=O)OCC
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(=O)c1ccc(Cl)c(F)c1
Reaction time: 3 h

Procedure:
Under argon atmosphere, to a solution of 4-chloro-3-fluoro-benzaldehyde (10 g) in N,N-dimethylformamide (50 ml) was added sodium cyanide (620 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hours. Then, to the mixture was added dropwise a solution of ethyl acrylate (5.2 ml) in N,N-dimethylformamide (25 ml), and the resulting mixture was stirred at the room temperature for 3 hours. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane:ethyl acetate=20:1) to obtain ethyl 4-(4-chloro-3-fluorophenyl)-4-oxobutyrate (9.4 g) as pale yellowish powder.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.[CH2:10]=O>O.[Pd]>[CH3:10][N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1
Reactant: C=O
Reactant: NC(=O)C1CCNCC1
Agent: [Pd]
Solvent: O
Product: CN1CCC(C(N)=O)CC1
Reaction time: 43 h
Yield: 64.5 %

Procedure:
Isonipecotamide (10 g, 78.0 mmoles) was dissolved in distilled water (100 mL) and 37% aqueous formaldehyde (7.6 mL, equivalent to 2.81 g HCHO, 93.6 mmoles) was added. Wet 10% Pd—C (8 spoon spatulas) was added under argon and the mixture was hydrogenated at 25° C. and 50 psi for 43 h. The catalyst was filtered off through Celite and the latter was washed with water and methanol. The combined filtrates were evaporated to dryness and the residue was chromatographed on a silica gel column (60×5 cm) using 8%–10%–20% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 1-methylisonipecotamide (7.15 g, 64%): FABMS: m/z 143.1 (MH+); HRFABMS: m/z 143.1184 (MH+). Calcd. for C7H15N2O: m/z 143.1184; δH (d6-DMSO) 1.50/1.57 (4H, m, CH2), 1.76/1.94 (4H, m, CH2), 2.10 (3H, s, —NCH3), 2.72 (1H, m, CH) and 6.68/7.18 ppm (2H, m, CONH2); δC (d6-DMSO) CH3: 41.2; CH2: 28.5, 28.5, 54.9, 54.9; CH: 46.2; C: 176.7.
Reaction SMILES: C(OC([CH:6]1[CH2:11][C:10]([C:18]#[N:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:8][C:7]1=[O:20])=O)C.Cl>C(O)(=O)C.O.[Na+].[Cl-]>[O:20]=[C:7]1[CH2:8][CH2:9][C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:18]#[N:19])[CH2:11][CH2:6]1
Reactant: CCOC(=O)C1CC(C#N)(c2ccccc2)CCC1=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CC1(c2ccccc2)CCC(=O)CC1
Temperature: 2.5 °C
Reaction time: 3.5 h

Procedure:
The title compound of step 1 (70.8 g, 261 mmol) in a mixture of acetic acid (810 mL) and concentrated hydrochloric acid (354 mL) was heated to boiling for 3.5 h under DC control. The mixture was then cooled to 0 to 5° C., diluted with water (1 L), saturated with NaCl and extracted cold with ethyl acetate (3×300 mL). The ethyl acetate phase was washed with water and concentrated to low volume in a vacuum. The solid residue was dissolved once again in ethyl acetate, washed with NaHCO3 solution and concentrated until dry.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[C:16]([N:19]([CH2:21][C:22](O)=[O:23])[CH3:20])(=[O:18])[CH3:17].[CH2:25]([O:27][C:28](=[O:38])[CH2:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:26]>CN(C)C=O.C(Cl)(Cl)Cl>[CH2:25]([O:27][C:28](=[O:38])[CH2:29][N:30]([C:22](=[O:23])[CH2:21][N:19]([C:16](=[O:18])[CH3:17])[CH3:20])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:26]
Reactant: CC(=O)N(C)CC(=O)O
Reactant: CCOC(=O)CNCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)CN(C)C(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A cold solution of 1.65 g DCC in 3 ml dimethylformamide is added to a stirred ice-cooled solution of 1.0 g N-acetylsarcosine and 1.4 g N-benzylglycine ethylester in 9 ml dry dimethylformamide, and the resulting solution is stirred at 0° C. for 1 hour and then at room temperature for 2 hours. It is then filtered and the precipitate is washed with dimethylformamide. The filtrate and washings are combined and the solvent is evaporated to dryness in vacuo to yield a residue which is then dissolved in 30 ml chloroform, washed with 5% aq. NaHCO3 and water, and dried over anhydrous MgSO4. Evaporation of solvent produces the desired ester which is either isolated (m.p. 98°-101° C.) or hydrolyzed directly to form the corresponding acid, N-(N'-acetylsarcosyl)-N-benzylglycine.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:9]([N:26](C)[CH2:27][CH2:28][NH2:29])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>N1CCCCC1.CN(C=O)C>[CH3:9][NH:26][CH2:27][CH2:28][NH:29][C:1](=[O:8])[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C(O)CCC(=O)O
Reactant: CN(CCN)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CNCCNC(=O)CCC(=O)O
Reaction time: 0.17 h

Procedure:
The support bound N-(Fmoc)-N-methyl ethylenediamine succinate (105) was treated with 20% piperidine/DMF (10 mL—applied and then allowed to drain). An additional amount of 20% piperidine/DMF (10 mL) was then added and the slurry was agitated for 10 minutes. The support was then washed with DMF (10 mL×2), CH2Cl2 (10 mL×2) and finally with DMF (10 mL×2). The deprotected support (106) was then immediately used in Step 5.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][C:9](O)=O)[CH2:3][C:4](O)=O.[NH2:12][NH:13][C:14]([NH2:16])=[S:15].O.[OH-].[Na+]>O=P(Cl)(Cl)Cl>[CH3:1][CH:2]([CH2:7][CH2:8][C:9]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1)[CH2:3][C:4]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1
Reactant: CC(CCC(=O)O)CC(=O)O
Reactant: NNC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(CCc1nnc(N)s1)Cc1nnc(N)s1
Temperature: 90 °C
Yield: 106.3 %

Procedure:
A mixture of 3-methyl adipic acid (5.00 g, 31.22 mmol) and thiosemicarbazide (5.69 g, 62.43 mmol) in POCl3 (45 mL) was heated at 90° C. for 4 h. The reaction was cooled to room temperature and poured into a mixture of ice and water. Sodium hydroxide pellets were added to the mixture until it was basic (pH 14). The white precipitate was collected by suction filtration, rinsed with water and dried to provide 5,5′-(2-methylbutane-1,4-diyl)-bis(1,3,4-thiadiazol-2-amine) (1003, 8.97 g). 1H NMR (300 MHz, DMSO-d6) δ 7.00 (s, 4H), 2.89-2.81 (m, 3H), 2.89-2.81 (m, 3H), 2.69 (dd, J=7.6, 7.6 Hz, 1H), 1.89-1.46 (m, 3H), 0.94 (d, J=6.6 Hz, 3H).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH:7]1[S:15][C:14]2[N:9]([C:10](=[O:20])[N:11]([CH2:17][CH2:18][CH3:19])[C:12](=[O:16])[CH:13]=2)[CH2:8]1>C(Cl)Cl>[Cl:3][CH2:6][CH:7]1[S:15][C:14]2[N:9]([C:10](=[O:20])[N:11]([CH2:17][CH2:18][CH3:19])[C:12](=[O:16])[CH:13]=2)[CH2:8]1
Reactant: CCCn1c(=O)cc2n(c1=O)CC(CO)S2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCn1c(=O)cc2n(c1=O)CC(CCl)S2
Temperature: 25 °C
Yield: 84 %

Procedure:
Thionyl chloride (0.61 ml)was added dropwise to a solution of 2-hydroxymethyl-6-propyl-2,3-dihydro-5H-thiazolo[3,2-c]pyrimidine-5,7(6H)-dione (1 g) in methylene chloride (15 ml) with stirring at room temperature, and the solution was refluxed for 16 hours. The solution was concentrated to dryness, and the resulting residue was purified by column chromatography on silica gel. The resulting crude crystals were recrystalized from methylene chloride-isopropyl ether to give colorless crystals (0.9 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][C:12]([CH2:13][Br:37])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OCc1ccc(-c2ccc(F)c(F)c2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(-c2ccc(CBr)cc2)cc1F
Temperature: 0 °C

Procedure:
Next, to a solution comprising 25 g of the previously obtained 4-(3,4-difluorophenyl)benzyl alcohol, 40 g of triphenylphosphine and 80 ml of dichloromethane was added dropwise a solution comprising 64 g of carbon tetrabromide and 35 ml of dichloromethane under stirring at 0° C. After completion of the dropwise addition, the mixture was stirred at the same conditions for one hour, and then raised to room temperature and stirred for one hour to react the materials. After completion of the reaction, the reaction mixture was extracted with hexane, washed with a saturated NaCl aqua, dried and the solvent was removed under reduced pressure, and the residue was purified by recrystallization to obtain 20 g of 4-(3,4-difluorophenyl)benzyl bromide.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Cl)[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[OH-].[NH4+:23]>O>[NH2:23][C:4]1[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([Br:1])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)nc2Cl)CC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)nc2N)CC1
Temperature: 120 °C
Reaction time: 12 h
Yield: 51 %

Procedure:
A 300 mL pressure vessel was charged with tert-butyl 4-(5-bromo-3-chloropyrazin-2-yl)piperazine-1-carboxylate (5.0 g, 13 mmol) and concentrated ammonium hydroxide (60 mL). The vessel was sealed and the reaction mixture was magnetically stirred at 120° C. for 12 h. After the reaction mixture was cooled to room temperature, the vessel was opened and the resulting mixture was poured into water (100 mL) and extracted with CH2Cl2 (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 3% EtOAc in CH2Cl2 (containing 2% Et3N), to afford 2.4 g (51%) of the product as a white solid. MS m/z: 358 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[N:6][CH:5]=[C:4](Cl)[N:3]=1.[CH3:17][NH:18][CH3:19]>>[NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[N:6][CH:5]=[C:4]([N:18]([CH3:19])[CH3:17])[N:3]=1
Reactant: Nc1nc(Cl)cnc1-c1cccc(Cl)c1Cl
Reactant: CNC
Product: CN(C)c1cnc(-c2cccc(Cl)c2Cl)c(N)n1

Procedure:
This compound was prepared in an analogous manner to the compound in Example 6 from 2-amino-6-chloro-3-(2,3-dichlorophenyl)pyrazine (Example 2) and dimethylamine (Aldrich). M.p. 147-148° C.
Reaction SMILES: [N+:1](=[C:3]1[C:20](=[O:21])[CH2:19][CH2:18][C@@:17]2([CH3:22])[C@H:4]1[CH2:5][CH2:6][C@@H:7]1[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]1[CH2:9][CH2:10][C@@H:11]2[OH:23])=[N-:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[N+:1](=[C:3]1[C:20](=[O:21])[CH2:19][CH2:18][C@@:17]2([CH3:22])[C@H:4]1[CH2:5][CH2:6][C@@H:7]1[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]1[CH2:9][CH2:10][C:11]2=[O:23])=[N-:2]
Reactant: C[C@]12CCC(=O)C(=[N+]=[N-])[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: C[C@]12CCC(=O)C(=[N+]=[N-])[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
4-Diazo-17β-hydroxymethyl-5αandrostan-3-one is oxidized with pyridinium chlorochromate according to the procedure described in Example 4 to give 4-diazo-3-oxo-5α-androstane-17β-carboxaldehyde. In a similar manner, 4-diazo-17β-hydroxy-5α-androstan-3-one is oxidized with pyridinium chlorochromate to give 4-diazo-5α-androstane-3,17-dione.