Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(#N)C.[CH:18]1(/[CH:22]=[CH:23]/[C:24]#[N:25])[CH2:21][CH2:20][CH2:19]1.N12CCCN=C1CCCCC2>>[CH:18]1([CH:22]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:23][C:24]#[N:25])[CH2:21][CH2:20][CH2:19]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#C/C=C/C1CCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1(C)OB(c2cnn(C(CC#N)C3CCC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.63 g, 0.0496 mol) in acetonitrile (124 mL, 2.37 mol) was added (E)-3-cyclobutylacrylonitrile (5.30 g, 0.0495 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (3.70 mL, 0.0248 mol). The resulting mixture was stirred at room temperature overnight, then evaporated to dryness. The mixture was purified on silica gel, eluting with 0 to 80% EtOAc in hexanes, to give the desired product as a racemic mixture (11.2 g, 75.2%). LCMS (M+H) 302.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:17]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: Clc1nc2ccccc2[nH]1
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1nc2ccccc2[nH]1
Temperature: 100 °C
Yield: 30.8 %

Procedure:
(RS)-2-Aminomethyl-piperidine-1-carboxylic acid tert butyl ester (0.25 g) and 2-chlorobenzimidazole (0.15 g) were combined and warmed to 100° C. for 48 hours. After cooling to room temperature the mixture was column chromatographed (silica gel, ethyl acetate/pentane 1:4—ethyl acetate/pentane 1:1 eluant) to give the title compound (0.1 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[Na].Cl.[CH2:8]([N:12]=[C:13]([NH2:22])[NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][Cl:21])[N:19]=1)[CH2:9][CH2:10][CH3:11].Cl>C(O)C.O>[ClH:21].[CH2:8]([N:12]=[C:13]([NH2:22])[NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][S:5][CH2:4][CH2:3][NH2:2])[N:19]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCN=C(N)Nc1nc(CCl)cs1
Reactant: NCCS
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCCCN=C(N)Nc1nc(CSCCN)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-aminoethanethiol hydrochloride (1.85 g.) in ethanol (30 ml.) was added to a stirred solution of sodium (0.90 g.) in ethanol (50 ml.) under a nitrogen atmosphere. A solution of 2-(2-n-butylguanidino)-4-chloromethylthiazole hydrochloride (2.20 g.) in ethanol (50 ml.) was added dropwise to the mixture, which was then stirred for 3 hours while warming to room temperature. A mixture of concentrated hydrochloric acid (5 ml.) and water (15 ml.) was then added, and the mixture evaporated to dryness. The residual gummy solid was extracted with boiling ethanol (3×20 ml.) and the residual white solid discarded. The combined ethanolic extracts were filtered and the filtrate evaporated to dryness to give 2-(2-n-butylguanidino)-4-(2-aminoethyl)thiomethylthiazole hydrochloride as a thick gum which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])([O-:3])=[O:2].[CH3:18][O:19][SiH:20]([O:23][CH3:24])[O:21][CH3:22]>[H+].[H+].O.O.O.O.O.O.Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH3:18][O:19][Si:20]([O:23][CH3:24])([O:21][CH3:22])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH2:6][C:5]1[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: C=CCCCCOCc1ccccc1[N+](=O)[O-]
Reactant: CO[SiH](OC)OC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: O
Product: CO[Si](CCCCCCOCc1ccccc1[N+](=O)[O-])(OC)OC
Temperature: 37 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
A 20-ml eggplant type flask was purged with nitrogen, and charged with 2.5 g (10.7 mmol) of 5-hexenyl 2-nitrobenzyl ether, 1.56 g (12.8 mmol) of trimethoxysilane, and an infinitesimal amount of hydrogen hexachloroplatinate(IV) hexahydrate (H2PtCl6·6H2O), followed by stirring at 37° C. for 30 minutes. Thereafter, the bath temperature was raised to 100° C., and the reaction was completed in 2 hours. After the temperature was returned to room temperature, the reaction mixture was purified by vacuum distillation using a short path. From the second fraction (0.2 mmHg/123–125° C.), 1.98 g of the desired product was obtained in a 52% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:18])=O)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:22].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>O1CCOCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:22]
Reactant: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1Cl
Reaction time: 2.5 h
Yield: 90 %

Procedure:
33.67 g (105 mmol) of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide were suspended in 140 ml of dioxan and 18 ml of pyridine and treated dropwise with 22.6 g (107.6 mmol) of trifluoroacetic anhydride at a temperature of <8° within 30 min. The mixture was stirred at 50° for 2.5 hours and poured into 700 ml of water. The suspension was filtered and, after drying the residue, there were obtained 28.62 g (90%) of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile of m.p. 225°-228°.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[C:9]([OH:17])[C:10](=[CH:15][CH:16]=1)[C:11](OC)=[O:12].[OH-].[NH4+:19]>CO>[NH2:6][C:7]1[CH:8]=[C:9]([OH:17])[C:10](=[CH:15][CH:16]=1)[C:11]([NH2:19])=[O:12]
Reactant: COC(=O)c1ccc(N)cc1O
Reactant: [NH4+]
Agent: O=S(=O)(O)O
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1ccc(N)cc1O
Reaction time: 8 h

Procedure:
Methyl 4-aminosalicylate bisulfate (5 g) is suspended in 20 mL of methanol. To the solution, 20 mL of 28% ammonium hydroxide is added slowly until all solid is dissolved. The reaction mixture is stirred at ambient conditions overnight. Solvent is removed under reduced pressure and water is lyophilized. The residue is collected, washed with minimum amount of ice water and dried to yield 2.5 g of the product as off-white powders.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[Br:12][CH2:13][CH2:14][CH2:15]Br>C(#N)C>[Br:12][CH2:13][CH2:14][CH2:15][O:11][C:3]1[CH:4]=[CH:5][C:6]([C:8](=[O:9])[CH3:10])=[CH:7][C:2]=1[CH3:1]
Reactant: BrCCCBr
Reactant: CC(=O)c1ccc(O)c(C)c1
Solvent: CC#N
Product: CC(=O)c1ccc(OCCCBr)c(C)c1

Procedure:
A mixture of 4-hydroxy-3-methylacetophenone (14.5 g, 96 mmol), K2 CO3 (17.5 g, 144 mmol), and 1,3-dibromopropane (30 g, 144 mmol) in acetonitrile (400 ml) was heated at reflux for 6 hours. At the end of the reaction, the solvent was removed on a rotary evaporator, and the crude solid was extracted into dichloromethane (750 ml). The insoluble inorganics were filtered off. The dichloromethane solution was concentrated again to a crude oil (34.5 g). Purification was effected by flash chromatography over a silica gel column (SiO2 150 g; eluted with 7:3 hexane:dichloromethane, 2 l; and dichloromethane 2 l). The material thus purified weighed 14.6 g (56%) and was recrystallized from ethanol. Recrystallization again from ethanol gave analytically pure 1-[4-(3-bromopropoxy)-3-methylphenyl]ethanone, m.p.=59°-61° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[CH2:5][CH:4]([CH2:16][N:17]([CH2:28][CH2:29]O)[C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:3]1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>ClCCl.[Cl-].[Na+]>[F:14][C:12]([F:13])([F:15])[C:9]1[CH:10]=[CH:11][C:6]2[CH2:5][CH:4]3[CH2:16][N:17]([C:18]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:27])[CH2:28][CH2:29][N:3]3[S:2](=[O:1])(=[O:31])[C:7]=2[CH:8]=1
Reactant: O=C(OCc1ccccc1)N(CCO)CC1Cc2ccc(C(F)(F)F)cc2S(=O)(=O)N1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCN2C(Cc3ccc(C(F)(F)F)cc3S2(=O)=O)C1
Reaction time: 3 h
Yield: 83.5 %

Procedure:
To a 0° C. solution of phenylmethyl [(3,4-dihydro-1,1-dioxido-7-(trifluoromethyl)-2H-1,2-benzothiazin-3-yl)methyl](2-hydroxyethyl)carbamate (400 mg, 0.873 mmol) in dichloromethane (20 mL, dried by passage through Act I neutral alumina) was added triethylamine (0.243 mL, 1.74 mmol) and methanesulfonic anhydride (228 mg, 1.31 mmol). After 3 h, an additional 70-mg portion of methanesulfonic anhydride was added. After an additional 1 h, a 228-mg portion of methanesulfonic anhydride and a 0.243-mL portion of triethylamine were added. After 10 min, the reaction was diluted with dichloromethane (20 mL), washed with saturated sodium bicarbonate (10 mL), dried (sodium sulfate) and concentrated in vacuo. To a 0° C. solution of this residue in tetrahydrofuran (10 mL) was added, dropwise, lithium bis(trimethylsilyl)amide (1 N in tetrahydrofuran, 1.10 mL, 1.10 mmol). After 20 min, an additional 0.15-mL portion of lithium bis(trimethylsilyl)amide was added dropwise to produce an orange solution. The reaction was diluted with saturated sodium chloride (20 mL). The aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by chromatography (silica, 10% ethyl acetate/hexanes to ethyl acetate gradient) to provide phenylmethyl 3,4,11,11a-tetrahydro-8-(trifluoromethyl)pyrazino[1,2-b][1,2]benzothiazine-2(1H)-carboxylate 6,6-dioxide (321 mg, 83%) as a white foam. LCMS (neg. ion spectrum) m/z 439.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([CH:10]2[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][NH2:23])[CH:18]=[CH:19][CH:20]=1.[BH4-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:9]=[C:8]([CH:10]2[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH2:4][NH:23][CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:24])[F:25])[CH:16]=1
Reactant: O=Cc1ccc(C2CC2)cc1Cl
Reactant: NCCc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: FC(F)(F)c1cccc(CCNCc2ccc(C3CC3)cc2Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.927 g of 2-chloro-4-cyclopropyl-benzaldehyde (5.37 mmol) and 1.52 g 2-(3-trifluoromethyl-phenyl)-ethylamine (8.05 mmol) were dissolved in 15 ml methanol and refluxed for 2 h. After cooling down to rt, the reaction mixture was treated in portions with 305 mg NaBH4, stirred at rt for 10 min and 12 h under reflux. The reaction mixture was then cooled to rt, treated with 1 ml 1N HCl and concentrated in vacuo. The resulting oil was then diluted with EtOAc, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (40 g silicagel, heltane/AcOEt 2:1) leading to 1.41 g (2-chloro-4-cyclopropyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine (74%) as a yellow oil. MS: 354 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2C)[N:3]=1.[Cl:17]C1C=CC(Cl)=CC=1C(O)=O>>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[Cl:17])[N:3]=1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)n1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Product: Clc1ccc(Cl)c(-c2nc(Cl)nc(Cl)n2)c1
Yield: 14 %

Procedure:
Using the method described for the synthesis of 2,4-dichloro-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine, 2,5-dichlorobenzoic acid afforded 2,4-dichloro-6-(2,5-dichloro-phenyl)-[1,3,5]triazine (2.2 g, 14% yield). 1H NMR (DMSO-d6) 8.10 (s, 1H), 7.50 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>C(#N)C.C1OCCOCCOCCOCCOCCOC1>[N:25]([CH2:2][C:3]1[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1)=[N+:26]=[N-:27]
Reactant: O=c1cc(CCl)n(Cc2ccccc2)cc1OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Product: [N-]=[N+]=NCc1cc(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Yield: 89.5 %

Procedure:
To a suspension of 2.0 g (6 mmol) of 2-(chloromethyl)-5-(phenylmethoxy)-1-(phenylmethyl)-4(1H)-pyridinone in 20 ml of acetonitrile was added 3.9 g (60 mmol) of sodium azide and 0.1 g of 18-crown-6, and the mixture was heated to reflux for four hours. The salts were filtered off by suction, and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate-methanol 8:2) yielding 1.86 g of the title compound, melting point 120° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[N:3]=1.[ClH:39].O1CCOCC1>C(OCC)(=O)C.C(OCC)C>[CH3:38][N:35]1[CH2:36][CH2:37][N:32]([C:4]2[CH:5]=[C:6]([N:8]3[CH:17]([CH3:18])[CH2:16][C:15]4[C:10](=[CH:11][C:12]([C:19]5[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=5)=[CH:13][CH:14]=4)[CH2:9]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:33][CH2:34]1.[ClH:39]
Reactant: CC1Cc2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1Cc2ccc(C3=CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
tert-Butyl 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-3,6-dihydropyridine-1(2H)-carboxylate (0.20 g, 0.38 mmol) in ethyl acetate (1.0 mL) was treated with 4.0 M of hydrogen chloride in 1,4-dioxane (1.0 mL, 4.0 mmol) at r.t. for 2 h. The mixture was diluted with ethyl ether, and centrifugalized. The solvents were decanted. The residue was dried in-vacuo to afford the desired product as HCl salt which was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=420.2.
Reaction SMILES: [CH3:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([F:11])[C:3]=1N.S(=O)(=O)(O)O.N([O-])=O.[Na+].[C-:21]#[N:22].[K+].[OH-].[NH4+]>S([O-])([O-])(=O)=O.[Cu+2].O>[CH3:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([F:11])[C:3]=1[C:21]#[N:22]
Reactant: Cc1c(N)c(F)cc(F)c1F
Reactant: [C-]#N
Agent: [Cu+2]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(F)c(F)cc(F)c1C#N
Yield: 38.2 %

Procedure:
To 2-methyl-3,4,6-trifluoroaniline (10.6 g) is added a mixture of conc. sulfuric acid (13.8 ml) and water (46 ml) and the mixture is cooled. Thereto an aqueous solution (20 ml) of sodium nitrite (5.5 g) is added dropwise at 0°-5° C. The solution is gradually added to a mixture of copper (II) sulfate 5 hydrate (41 g), potassium cyanide (43 g), ammonium hydroxide (60 ml) and water (260 ml) at 10°-30° C. The mixture is extracted with dichloromethane and the extract is dried over sodium sulfate, concentrated and the residue is purified with column chromatography (silica-gel, dichloromethane:n-hexane=1:4) to give 2-methyl-3,4,6-trifluorobenzonitrile (4.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([S:13][CH3:14])[N:3]=1.C(Cl)Cl.[NH2:18][CH2:19][C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(N(CC)CC)C>O>[Cl:1][C:2]1[C:7]([C:8](=[O:9])[NH:18][CH2:19][C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[C:6]([O:11][CH3:12])[N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: COc1nc(SC)nc(Cl)c1C(=O)Cl
Reactant: NCc1ncccn1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1nc(SC)nc(Cl)c1C(=O)NCc1ncccn1
Reaction time: 0.33 h

Procedure:
To a mixture of whole amount of 4-chloro-5-chloroformyl-6-methoxy-2-methylthiopyrimidine (prepared in the above (4)) and methylene chloride 10 ml is dropped a mixture of 2-aminomethylpyrimidine 930 mg, triethylamine 2.38 ml and methylene chloride 10 ml over a period of 5 minutes on an ice bath, and the mixture is stirred for 20 minutes. The mixture is further stirred at room temperature for 40 minutes. The reaction mixture is diluted with water and the water layer is extracted with methylene chloride. The organic layer is dried and concentrated in vacuo. The residue is separated with silica gel chromatography (solvent; chloroform:ethyl acetate=1:1) and recrystallized from a mixture of methylene chloride, ethyl acetate and isopropyl ether to give 4-chloro-5-[N-(2-pyrimidinylmethyl)carbamoyl]-6-methoxy-2-methylthiopyrimidine as a colorless crystalline powder, 1.56 g. mp 176-177° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:6]([CH3:22])=[C:7]2[C:11](=[C:12]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]=1[CH3:14])[NH:10][CH2:9][CH2:8]2)[CH3:3].I[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].CCOC(C)=O>CN(C=O)C>[CH2:24]([N:10]1[C:11]2[C:7](=[C:6]([CH3:22])[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])=[C:13]([CH3:14])[C:12]=2[NH:15][C:16](=[O:21])[C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:8][CH2:9]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCI
Reactant: Cc1c(CN(C)C)c(C)c(NC(=O)C(C)(C)C)c2c1CCN2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCN1CCc2c(C)c(CN(C)C)c(C)c(NC(=O)C(C)(C)C)c21
Reaction time: 0.5 h
Yield: 120.4 %

Procedure:
N-(5-Dimethylaminomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (700 mg) was dissolved in DMF (7 ml) and Na (P=60%, 160 mg) was added under a nitrogen atmosphere at 5° C. After stirring at the same temperature for 30 min, 1-iodooctane (240 mg) was added, which was followed by stirring at 30° C. for 3 hr. AcOEt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=10/1-3/1) to give 500 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]#[C:12][C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:6]2[CH3:19].[S:27](=O)(=[O:30])([OH:29])[OH:28]>CO>[S:27]([O:18][C:13]1([C:12]#[C:11][C:9]2[N:8]=[C:7]3[C:3]([N:4]=[C:5]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=4)[N:6]3[CH3:19])=[C:2]([NH2:1])[N:10]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1)([OH:30])(=[O:29])=[O:28]
Reactant: Cn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC3(O)CCCC3)nc21
Reactant: O=S(=O)(O)O
Solvent: CO
Product: Cn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC3(OS(=O)(=O)O)CCCC3)nc21
Yield: 92.5 %

Procedure:
1-{2-(6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol (1.59 g) was suspended in 10 mL of methanol and 1 mL of a methanol solution of 440 mg of concentrated sulfuric acid was added dropwise thereinto at room temperature. The resulting solution was evaporated until the amount of the solution became about one half followed by adding 4 mL of ether thereto. The resulting crystals were collected by filtration, washed with ether and dried to give 1.79 g of the sulfate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.O.[CH3:11]C1C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:11])=[O:8])[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1CCOCC1
Solvent: O
Solvent: CO
Product: COC(=O)C1CCOCC1
Yield: 15 %

Procedure:
To a solution of tetrahydro-2H-pyran-4-carboxylic acid (50 g, 385 mmol) in anhydrous methanol (500 mL) was added 4-methylbenzenesulfonic acid hydrate (72.5 g, 385 mmol). The mixture was refluxed for 2 hr. The solvent was removed in vacuo. Ethyl ether and water was added. The organic phase was washed with water and brine, then dried over Na2SO4, filtered and concentrated to give methyl tetrahydro-2H-pyran-4-carboxylate (8.3 g, 75%), which was used in next step without purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[OH-:15].[Na+].Cl>CS(C)=O>[CH3:13][CH:12]([O:11][C:4]1[CH:3]=[C:2]([OH:15])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[CH3:14]
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)Oc1cc(O)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
To a solution of 4-fluoro-2-(1-methylethoxy)-1-nitrobenzene (20.34 g) in dimethylsulfoxide (150 mL) was added 20% aqueous sodium hydroxide solution (68 mL) at room temperature and the mixture was stirred at 60° C. for 3 h. The mixture was cooled to room temperature and 6M hydrochloric acid (50 mL) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual oil was solidified with hexane to give the title compound (14.94 g, 74%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.FC(F)(F)C(O)=O.[CH3:48][O:49][C:50](=[O:71])[C@H:51]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[NH:52][C:53](=[O:63])[C@H:54]([CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[NH2:55].C(N1CCOCC1)C>CN(C)C=O>[CH3:48][O:49][C:50](=[O:71])[C@H:51]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[NH:52][C:53](=[O:63])[C@H:54]([CH2:56][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)[NH:55][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred, cooled (0° C.) solution of benzyloxycarbonylglycine (955mg, 4.5 mmole) and 1-hydroxybenzotriazole (1.2 g, 9 mmole) in dimethylformamide (15 ml) is added dicyclohexylcarbodiimide (1.03 g, 5 mmole). The mixture is stirred for 1 hour at 0° C. A cooled solution of phenylalanyl-phenylalanine methyl ester trifluoroacetate (2.0 g, 4.5 mmoles, described in U.S. Pat. No. 3,917,578, noted above) in dimethylformamide (20 ml) and N-ethyl morpholine (0.58 ml) is added and the mixture is stirred overnight at room temperature. The mixture is filtered and the filtrate is evaporated. The residue is dissolved in ethyl acetate (100 ml) and the solution is filtered. The filtrate is washed with 10% aqueous citric acid solution, saturated sodium chloride solution, saturated sodium bicarbonate solution and saturated sodium chloride solution. The solution is dried over magnesium sulfate (anhydrous) and evaporated. The residue is crystalized from ethyl acetate-petroleum ether (30°-60°) to give the title compound as crystals, mp 122°-124° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[N:16]O)[CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])[CH3:3]>C(O)C.[Rh]>[CH3:3][C:2]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][CH2:10][CH:11]([NH2:16])[CH2:12][CH:13]([CH3:14])[CH3:15])([CH3:1])[CH3:4]
Reactant: CC(C)CC(CCCNC(=O)OC(C)(C)C)=NO
Agent: [Rh]
Solvent: CCO
Product: CC(C)CC(N)CCCNC(=O)OC(C)(C)C

Procedure:
A solution of E and Z isomers of 4-(hydroxyimino)-6-methylheptylcarbamic acid 1,1-dimethylethyl ester (2.1 g, 8.13 mmol) in ethanol (75 ml) was hydrogenated at 5 bar pressure over rhodium on alumina (200 mg) for 36 h. The mixture was then filtered and the filtrate concentrated to dryness to afford the title compound in quantitative yield (2 g).