Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH3:27][C@@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[CH2:30][S:29]1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][C:53]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([Cl:65])[CH:60]=2)([C:56](O)=[O:57])[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:65][C:61]1[CH:60]=[C:59]([C:53]2([C:56]([N:40]3[CH2:41][CH2:42][N:37]([C:35]4[C:36]5[C@@H:28]([CH3:27])[S:29][CH2:30][C:31]=5[N:32]=[CH:33][N:34]=4)[CH2:38][CH2:39]3)=[O:57])[CH2:52][CH2:51][N:50]([C:48]([O:47][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:49])[CH2:55][CH2:54]2)[CH:64]=[CH:63][CH:62]=1
Reactant: C[C@H]1SCc2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2cccc(Cl)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1SCc2ncnc(N3CCN(C(=O)C4(c5cccc(Cl)c5)CCN(C(=O)OC(C)(C)C)CC4)CC3)c21
Reaction time: 18 h

Procedure:
HBTU (0.07726 g, 0.2037 mmol) was added to a solution of (R)-5-methyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (0.030 g, 0.09701 mmol), 1-(tert-butoxycarbonyl)-4-(3-chlorophenyl)piperidine-4-carboxylic acid (0.06593 g, 0.1940 mmol), and DIEA (0.06759 ml, 0.3880 mmol) in DCM (2.5 mL). The reaction mixture was stirred overnight (18 hours), after which, saturated NaHCO3 was added. The mixture was extracted with DCM, and the extracts were dried (Na2SO4), filtered, and concentrated. The crude was flashed on Biotage 12M (DCM flushed to remove DIEA, then 2:1 to 1:1 DCM:EA; top spot [by-prod] eluted quickly, then 2nd spot [prod]) to give (R)-tert-butyl 4-(3-chlorophenyl)-4-(4-(5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carbonyl)piperidine-1-carboxylate. This was dissolved in dioxane (2 mL), and 4M HCl/dioxane (0.7275 ml, 2.910 mmol) was added, causing slow precipitation. The reaction mixture was stirred at room temperature overnight (18 hours), after which it was concentrated to dryness. The solids were dissolved in minimal MeOH, and then the product was triturated by the addition of ether. The resulting solids were isolated by filtration thru medium frit funnel with nitrogen pressure, rinsed with ether, and dried in vacuo to give (R)-(4-(3-chlorophenyl)piperidin-4-yl)(4-(5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)methanone dihydrochloride (0.029 g, 56.31% yield) as a pale yellow powder.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[CH:11]1([C@@:14]2([OH:21])[C@H:18]([CH3:19])[NH:17][C:16](=[O:20])[CH2:15]2)[CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:10][C:4]1[CH:3]=[C:2]([N:17]2[C:16](=[O:20])[CH2:15][C@:14]([CH:11]3[CH2:13][CH2:12]3)([OH:21])[C@@H:18]2[CH3:19])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: C[C@@H]1NC(=O)C[C@@]1(O)C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@@H]1N(c2ccc(C#N)c(Cl)c2)C(=O)C[C@@]1(O)C1CC1

Procedure:
Using 4-bromo-2-chlorobenzonitrile (424 mg), (4R,5S)-4-cyclopropyl-4-hydroxy-5-methylpyrrolidin-2-one (350 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (166 mg), tris(dibenzylideneacetone)dipalladium(0) (86 mg) and cesium carbonate (902 mg), and in the same manner as in Example 62, the title compound was obtained as a white powder (yield: 58 mg, 11%).
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][C:12](=[N:17][OH:18])[C:13]2=[O:16])=[CH:9][CH:8]=1.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>O>[Si:24]([O:18][N:17]=[C:12]1[CH2:11][C:10]2[C:14](=[CH:15][C:7]([CH3:6])=[CH:8][CH:9]=2)[C:13]1=[O:16])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc2c(c1)C(=O)C(=NO)C2
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C(=O)C(=NO[Si](C)(C)C(C)(C)C)C2
Temperature: 95 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To N,N-dimethylformamide (50 ml) were added at room temperature the compound (4.36 g, 24.9 mmol) obtained in step A, imidazole (5.10 g, 74.7 mmol) and tert-butyldimethylsilyl chloride (5.60 g, 37.4 mmol), and the mixture was stirred at 95° C. for 2 hr. After cooling to room temperature, water was added to the reaction solution with stirring and the precipitated solid was filtered, washed with water, and dried under reduced pressure to give the title compound (6.00 g, yield 83%) as a pale-bistered solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S-:8][C:9]#[N:10].[NH4+].BrBr.C(=O)(O)[O-].[Na+]>CO.[Br-].[Na+].CCCCCC.CCOCC.O>[S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[C:9]#[N:10]
Reactant: N#C[S-]
Reactant: Nc1ccccc1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: CCCCCC
Solvent: CO
Product: N#CSc1ccc(N)cc1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a -10° C., mechanically-stirred solution of aniline (21 g) and ammonium thiocyanate (52.1 g) in methanol (230 mL) was added a solution of bromine (38.7 g) in sodium bromide-saturated methanol. The rate of addition was adjusted such that the temperature of the reaction mixture did not rise above 0° C. After the addition was complete, the reaction mixture was stirred for one hour. The reaction mixture was then poured into a mixture of water (one liter), saturated aqueous sodium bicarbonate (500 mL) and ether (500 mL). The reaction mixture was then stirred for one hour and the phases separated. The organic phase was washed with brine, dried over magnesium sulfate and concentrated to yield an oil, which solidified upon trituration with hexane. The resulting solid was filtered and washed with hexane to afford 30.5 g of 4-thiocyanoaniline. Condensation of 4-thiocyanoaniline (5.7 g) with cyanoacetic acid, as described in Preparation 1, afforded 5.1 g of the title compound, α-cyano-4-thiocyanoacetanilide; m.p. 165°-166° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[N:6][CH:7]=1.[Li]CCCC.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([O:31][CH3:32])=[C:27]([CH:30]=1)[CH:28]=[O:29]>C1COCC1.CCCCCC>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([O:31][CH3:32])=[C:27]([CH:28]([C:2]2[CH:7]=[N:6][C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])=[CH:4][CH:3]=2)[OH:29])[CH:30]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: Fc1ccc(Nc2ccc(Br)cn2)c(F)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1C(O)c1ccc(Nc2ccc(F)cc2F)nc1
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
(5-Bromo-pyridin-2-yl)-(2,4-difluoro-phenyl)-amine (100 mg; 0.35 mmol) in THF (2.2 ml) is treated at −78 C with nBuLi (0.48 ml of a 1.5M solution in hexane; 0.77 mmol). After 10 min at −78 C, 5-bromo-2-methoxybenzaldehyde (75 mg; 0.35 mmol) in THF (0.3 ml) is added and stirring continued for 30 min. at −78 C. The reaction mixture is poured on water/ice and extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4 and evaporated to dryness. Purification via chromatography (SiO2; TBME/hexanes 3/7) yields the title compound (60 mg; 40%)
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([O:14][C:15](=[O:25])[CH2:16]P(OCC)(OCC)=O)[CH3:13].[Cl:26][C:27]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]([CH3:38])[C:28]=1[CH:39]=O>C1COCC1>[CH2:12]([O:14][C:15](=[O:25])[CH:16]=[CH:39][C:28]1[N:29]([CH3:38])[C:30]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[N:31][C:27]=1[Cl:26])[CH3:13]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cn1c(-c2ccccc2)nc(Cl)c1C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1c(Cl)nc(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.72 ml of a 1.6 M solution of n-butyllithium in n-hexane (4.4 mmol) were added at 0° C. to a solution of 1.219 g (5.4 mmol) of diethylphosphonoacetic acid ethyl ester in 30 ml of dry THF. After stirring at 0° C. for 30 min, 0.8 g (3.8 mmol) of 5-chloro-3-methyl-2-phenyl-3H-imidazole-4-carbaldehyde in 10 ml of THF were added. The reaction mixture was allowed to stand overnight and then concentrated. The residue was taken up in 100 ml of ethyl acetate, and the solution washed three times with 30 ml each of a sodium hydrogencarbonate solution, dried with magnesium sulfate and evaporated. The obtained crude 3-(5-chloro-3-methyl-2-phenyl-3H-imidazol-4-yl)-acrylic acid ethyl ester was stirred in 5.4 ml of 1 N sodium hydroxide solution and 20 ml of tert-butanol at room temperature for 24 h. After concentration, 10 ml of water were added, and the mixture was acidified to pH=5 with hydrochloric acid. The mixture was stirred for 1 h, and the precipitated product was filtered off with suction and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.[NH2:43][CH:44]1[CH2:49][CH2:48][N:47](C(OC(C)(C)C)=O)[CH2:46][CH2:45]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([NH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)NC1CCNCC1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and 4-amino-1-tert.-butyloxycarbonyl-piperidine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [C:1]12([OH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.ClC(Cl)(Cl)[C:14]([N:16]=C=O)=[O:15].CO.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:14](=[O:15])([O:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)[NH2:16]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: NC(=O)OC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
1-Adamantanol (1.52 g, 10.0 mmol) in dichloromethane (30 mL) was mixed with trichloroacetyl isocyanate (1.40 mL, 11.8 mmol) at 0° C., then warmed to room temperature and stirred for 2 hours. After completion of the reaction, the reaction solution was evaporated under reduced pressure, and the resulting crude reaction product was mixed with methanol (15 mL) and saturated aqueous potassium carbonate and stirred at 50° C. for 1 day. After completion of the reaction, the methanol was removed by vacuum distillation, and the residue was filtered. The resulting solid was washed with water and dried under reduced pressure to give the desired product (74% yield, 2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH3:15][C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([CH3:25])=[CH:20][CH:19]=2.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH3:25])[CH:22]=3)[NH:17][C:16]=2[CH3:15])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: Cc1ccc2[nH]c(C)cc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1ccc2[nH]c(C)c(C(=O)c3ccc(Cl)c(S(N)(=O)=O)c3)c2c1

Procedure:
is obtained as described in Example 10 (a) from 10 g 4-chloro-3-sulfamoylbenzoyl chloride and 7.8 g 2,5-dimethylindole in dichloro-ethane in the presence of 12 g aluminum chloride. M.p. 248°-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=O)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:12]1[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:10][C:11]=1[C:15]#[N:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1Cl
Temperature: 100 °C

Procedure:
To the product of Step C of Example 129 (1.50 g, 4.40 mmol) was added POCl3 (5 mL, 53.6 mmol). The mixture was heated to 100° C. for 17 hours before concentrating in vacuo. The residue was dissolved in ethyl acetate and washed with NaHCO3 (saturated, aq.), water, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica gel) eluting with 10% ethyl acetate/hexane affording product. MS (electrospray) m/e 360.9 MH+ (Rt=4.1 min LC/MS).
Reaction SMILES: ClC(OCC(C)C)=O.[NH:9]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:10]([C:26]([OH:28])=O)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].CN1CCOCC1.[NH2:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([O:59][CH3:60])=[O:58])[CH2:53][CH:54]([CH3:56])[CH3:55])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47].Cl>C(OCC)(=O)C>[NH:9]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:10]([C:26]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([O:59][CH3:60])=[O:58])[CH2:53][CH:54]([CH3:55])[CH3:56])=[O:50])[CH2:45][CH:46]([CH3:47])[CH3:48])=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
Isobutyl chloroformate (13.66 g, 100 mmol) was added dropwise over 15 min at -15 to -10° C. to a solution of Boc-Lys(Z)-OH (38.04 9, 100 mmol) in ethyl acetate (200 g). Another portion of ethyl acetate was added (10 g) and the mixture was stirred for 15 min. 4-Methylmorpholine (10.12 g, 100 mmol) was added dropwise over 15 min at -15 to -10° C., followed by an additional portion of ethyl acetate (10.0 g) and the resulting mixture was stirred for 2 h. In a separate reaction vessel 4-methylmorpholine (10.12 g, 100 mmol) was added dropwise over 15 min, to a solution of H-Leu-Leu-OMe·HCl (29.48 g, 100 mmol) in ethyl acetate (200.0 g) at -23 to -10° C. An additional portion of ethyl acetate (10.0 g) was added followed by the addition of the formed anhydride over 30 to 45 min at a temperature of -8 to -10° C. Another portion of ethyl acetate (30.0 g) was added and the resulting mixture was stirred for 1.5 h. Ethyl acetate (50.00 g) was added, the solution was filtered and the resulting organic filtrate was concentrated in vacuo. The resulting solid was recrystallized from petroleum ether (bp 100 to 125) to give Boc-Lys(Z)-Leu-Leu-OMe (55.9 g, 90.2%).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[C:10](=[NH:20])(OCC)[CH2:11][C:12](=[NH:16])OCC.[C:21]1([NH:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[NH2:16][C:12]1[CH:11]=[C:10]([NH2:20])[N:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:28]=1
Reactant: CCOC(=N)CC(=N)OCC
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1cc(N)n(-c2ccccc2)n1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (6 ml) was added over 5 minutes to a stirred suspension of diethyl malonimidate dihydrochloride (5 g) in ethanol (50 ml). Phenylhydrazine (2.1 ml) was added, then the mixture was stirred at ambient temperature for 4 hours and at 95° C. for 30 minutes. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate (100 ml) and water (50 ml). The organic layer was separated, washed with water (50 ml), dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by flash chromatography over silica using a 19:1 mixture of dichloromethane and methanol as eluant, appropriate fractions were combined, and the solvents were removed in vacuo to give 3,5-diamino-1-phenylpyrazole as a red-brown oil (0.76 g).
Reaction SMILES: [CH:1]([N-]C(C)C)([CH3:3])[CH3:2].[Li+].[CH:9]12[CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][C:10]2=[O:16].C(Br)C=C.Cl>O1CCCC1.CCCCCC.O1CCCC1>[CH2:3]([CH:11]1[CH:12]2[CH2:15][CH:9]([CH2:14][CH2:13]2)[C:10]1=[O:16])[CH:1]=[CH2:2]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1CC2CCC1C2
Agent: Cl
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC1C(=O)C2CCC1C2
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To 3.4 ml (6.8 mmol) of a 2M solution of lithium diisopropyl amide in tetrahydrofuran-hexane, 1 ml of a solution of 500 mg (4.54 mmol) of (-)-2-norbornanone in tetrahydrofuran was added dropwise at -40° C., and the mixture was stirred at -20° C. for 10 minutes. Then, 1 ml of a solution of 540 mg (4.46 mmol) of allyl bromide in tetrahydrofuran was added dropwise, the mixture was stirred at -20° C. for 30 minutes, the temperature of the mixture was raised to room temperature, and the mixture was stirred for one hour. On ice cooling, the reaction mixture was poured into 20 ml of 1N hydrochloric acid, and the mixture was extracted with toluene (50 ml×4). The extract was washed with successive, saturated sodium bicarbonate solution, water, saturated sodium chloride (each 50 ml), and dried over anhydrous magnesium sulfate. The solution was filtered, and the solvent was distilled off to obtain 980 mg of crude 3-allyl-2-norbornanone. The product was purified by distillation, and 550 mg (3.66 mmol) of (-)-exo-3-allyl-2-norbornanone was obtained. Yield: 81%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7].[I-:15].[Na+]>CC(C)=O>[I:15][CH2:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7]
Reactant: [I-]
Reactant: C=CCOC(=O)c1cccc(CCl)c1
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCOC(=O)c1cccc(CI)c1

Procedure:
A solution of allyl 3-(chloromethyl)-benzoate (54.5 g, 0.259 mmol) and sodium iodide (46.56 g, 0.311 mol) in acetone (500 mL) is stirred at room temp. for 6.5 hours, after which time the mixture is filtered. The filitrate is evaporated and the residue is dissolved in diethyl ether (500 mL), then washed with water (1×200 mL), 5% sodium sulfite solution (1×200 mL) and brine (1×200 mL), dried over magnesium sulfate, and evaporated to yield allyl 3-(iodomethyl)-benzoate as a white solid, which was is directly.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.CO>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][O:13][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[C@@H:9]([OH:10])[CH2:8]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1Br
Solvent: CO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](n3cc(Br)c(N)nc3=O)C[C@@H]2O)cc1
Reaction time: 22 h
Yield: 49.1 %

Procedure:
A solution of 3.06 g of 5-bromo-2'-deoxycytidine and 2.3 g of p-toluenesulfonyl chloride in 50 ml of pyridine was stirred at 4° C. for 24 hours. An additional 1.91 g of p-toluenesulfonyl chloride were added and stirring was continued at 4° C. for an additional 22 hours. 20 ml of methanol were added, the mixture was stirred at room temperature for 30 minutes and then evaporated. The crude product was subjected to flash chromatography on a column of silica gel using ethyl acetate/methanol (9:1) for the elution, there being obtained 2.26 g of 5-bromo-2'-deoxy-5'-O-p-toluenesulfonylcytidine in the form of a white solid of melting point 168° C. (decomposition).
Reaction SMILES: [CH3:1][CH:2]([C:6](Cl)=O)[C:3](Cl)=[O:4].[C:9]([CH:12]([C@@H:14]1C[CH2:17][CH2:16][NH:15]1)C)(O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+].Cl>ClCCl>[CH3:1][CH:2]1[C@H:6]2[N:15]([CH2:14][CH2:12][CH2:9]2)[CH2:16][CH2:17][C:3]1=[O:4]
Reactant: CC(C(=O)Cl)C(=O)Cl
Reactant: CC(C(=O)O)[C@@H]1CCCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1C(=O)CCN2CCC[C@@H]12
Reaction time: 0.25 h
Yield: 171.6 %

Procedure:
2.01 ml (18.7 mmol) of methyl malonyl chloride were added dropwise to a stirred, ice-cooled mixture of a solution of 2.43 g (17.0 mmol) of (2S)-2-(1-carboxyethyl)pyrrolidine [prepared as described in Tetrahedron Lett., 40, 2891–2894 (1999)] in 60 ml of dichloromethane and 2.61 ml (18.7 mmol) of triethylamine. After stirring the resulting mixture at the same temperature for 15 minutes and then at room temperature for 30 minutes, a saturated aqueous solution of sodium hydrogencarbonate was added. Subsequently, the resulting mixture was adjusted to pH 2 with concentrated hydrochloric acid and then extracted with a 4:1 by volume mixture of dichloromethane and isopropanol. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure to afford 4.47 g (yield: quantitative) of the title compound as a pale brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([OH:26])=[O:25])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[NH:31][C:32](=[NH:44])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[C:32]([NH:44][O:25][C:24]([C:23]1[CH:22]=[C:21]([CH:29]=[CH:28][CH:27]=1)[CH2:20][N:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:26])(=[NH:31])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCCCCC(=N)NO
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)cc1)Cc1cccc(C(=O)O)c1
Product: CCCCCCCCCCCC(=N)NOC(=O)c1cccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)c1
Yield: 99 %

Procedure:
The same procedure as employed in the preparation of Example 10 (step a) but using 3-({(tert-butoxycarbonyl)[4-(trifluoromethyl)benzyl]amino}methyl)benzoic acid and N-hydroxydodecanimidamide gave the title compound as a pale yellow oil (99%). 1H NMR (CDCl3, 300 MHz) δ 7.91 (m, 2H), 7.59 (m, 2H), 7.36 (m, 4H), 4.78 (br s, 2H), 4.48 (br s, 2H), 4.41 (br s, 2H), 2.34 (m, 2H), 1.65 (m, 2H), 1.50 (s, 9H), 1.26 (br s, 16H), 0.88 (m, 3H). HPLC (Condition A), Rt: 7.34 min (HPLC purity: 95.6%).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:17])[F:16])[NH:11][C:10]=2[C:9](=[O:19])[NH:8][C:7]1=[S:20])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].S(OC)(O[CH3:27])(=O)=O>O>[CH3:27][S:20][C:7]1[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:16])[F:17])[NH:11][C:10]=2[C:9](=[O:19])[N:8]=1
Reactant: COS(=O)(=O)OC
Reactant: CCCCCn1c(=S)[nH]c(=O)c2[nH]c(C(F)(F)F)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCn1c(SC)nc(=O)c2[nH]c(C(F)(F)F)nc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.7 %

Procedure:
To the solution of 3-pentyl-2-thioxo-8-(trifluoromethyl)-1,2,3,7-tetrahydro-6H-purin-6-one (600 mg, 2 mmol) in a 2 M solution of sodium hydroxide in water (12.0 mL) was added dimethyl sulfate (0.30 mL, 3.2 mmol). The reaction mixture was stirred at room temperature for 1.5 h and quenched with acetic acid. The resulting solution was extracted with methylene chloride three times. The combined organic layer was dried, filtered and concentrated to give the desired product (0.60 g, 95.6%). LCMS calculated for C12H16F3N4OS: (M+H) 321.1. Found 321.1.