Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:18][N:6]2[C:7](=[O:17])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:10]=[C:5]2[NH:4][CH2:3]1.CS(O[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33])(=O)=O.[F-].[K+]>C(#N)C>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][CH2:25][CH2:24][N:4]1[C:5]2=[N:10][C:9]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)=[CH:8][C:7](=[O:17])[N:6]2[CH2:18][CH:2]([OH:1])[CH2:3]1
Reactant: O=c1cc(-c2ccncc2)nc2n1CC(O)CN2
Reactant: CS(=O)(=O)OCCCc1ccccc1F
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: O=c1cc(-c2ccncc2)nc2n1CC(O)CN2CCCc1ccccc1F
Temperature: 80 °C

Procedure:
A suspension of 1.0 g (4.09 mmol) of 7-hydroxy-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one and 0.95 g (4.09 mmol) of 1-[3-(methylsulfonyloxy)propyl]-2-fluorobenzene in 100 ml of anhydrous acetonitrile was treated with 4.1 g (1.42 mmol) of potassium fluoride suspended on alumina (Fluka) and the resulting mixture was heated at 80° C. for 24 h.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[CH:16]([C:18]([CH3:20])=[O:19])=[CH2:17].[OH-].[K+]>C1COCC1.C(O)C>[O:19]=[C:18]1[CH2:16][CH2:17][C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH:1]=[CH:20]1
Reactant: C=CC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(C=CC(=O)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To the solution of tert-butyl 4-formylpiperidine-1-carboxylate (5.87 mmol, 1 eq) in THF (250 ml) was added methyl vinyl ketone (7.63 mmol, 1.3 eq) at 0° C., followed by slow addition of 3 N KOH in ethanol (7.7 ml). The reaction was then stirred at 25° C. for 16 h. The reaction mixture was concentrated to one-third of the volume of solvent and then acidified with 0.5 N HCl at 0° C. The aqueous layer was extracted with ethyl acetate (2×100 ml), and the organics dried over Na2SO4 and concentrated. The crude material was used in the next step without further purification. Yield: 91%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:16]1([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17]1)=O.O=P(Cl)(Cl)Cl.Cl>C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:14]([C:16]3([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17]3)[NH:13][CH2:12][CH2:11][C:5]2=1
Reactant: CCOC(=O)C1(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)CCC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Reaction time: 3 h

Procedure:
32 g of the product obtained in Step A are heated at reflux in a solution of 400 ml of toluene and 35 ml of POCl3. After 3 hours, the reaction mixture is concentrated under reduced pressure, the residue is taken up in 300 ml of ethanol, and 5 g of sodium borohydride are slowly added. After 30 minutes, 300 ml of water are added and the ethanol is distilled off. After extraction of the residue with dichloromethane, drying and evaporation under reduced pressure, the oily residue obtained is converted into the hydrochloride in an ethanolic hydrogen chloride solution. The expected product is isolated by filtration and drying in vacuo.
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=C)[C:13]([OH:15])=[O:14].CSC>ClCCl>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:1])[C:13]([OH:15])=[O:14]
Reactant: C=C(C(=O)O)c1ccccc1OC
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CSC
Product: COc1ccccc1C(=O)C(=O)O
Yield: 69 %

Procedure:
A stream of ozone is sparged at -75° C. for 3 hours 30 minutes into a solution of 1 g (5.62 mmol) of 2-(2-methoxyphenyl)acrylic acid, obtained under the conditions described in Example 38, in dichloromethane. 1.66 cm3 (22.5 mmol) of dimethyl sulphide are added and stirring is continued, the temperature being allowed to rise to the region of 20° C. After concentrating the reaction mixture to dryness, 0.7 g (69%) of (2-methoxyphenyl)oxoacetic acid is obtained in the form of crystals, the characteristics of which are as follows: mass spectrum (E.I.) M/Z=180 (M+)
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=2)=[CH:20]1.[F:32][C:33]([Si](C)(C)C)([F:35])[F:34].Cl>C1COCC1>[F:32][C:33]([F:35])([F:34])[CH:28]([C:27]1[CH:30]=[CH:31][C:24]([C:21]2[CH:22]=[CH:23][O:19][CH:20]=2)=[CH:25][CH:26]=1)[OH:29]
Reactant: O=Cc1ccc(-c2ccoc2)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(-c2ccoc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
Tetrabutylammonium fluoride (0.024 ml; 1.0 M solution in tetrahydrofuran) was added to a solution of 4-furan-3-yl-benzaldehyde (410 mg, 2.38 mmol) and trifluoromethyltrimethylsilane (TMSCF3) (423 μl, 2.86 mmol) in 5 ml THF at 0° C. The formed mixture was warmed up to room temperature and stirred at room temperature for 4 hours. The reaction mixture was then treated with 5 ml of 1N HCl and stirred at room temperature overnight. The product was extracted with ethyl acetate (3×50 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 480 mg of 2,2,2-trifluoro-1-(4-furan-3-yl-phenyl)-ethanol, yield: 83%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][CH:8]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[CH2:11][CH2:10][N:9]2[CH3:17])=[CH:5][CH:4]=1.[CH:20]#[CH:21].N>CCOCC>[C:20]([C:12]1([OH:16])[CH2:11][CH2:10][N:9]([CH3:17])[CH:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=2)[C:13]1([CH3:15])[CH3:14])#[CH:21]
Reactant: COc1ccc(CC2N(C)CCC(=O)C2(C)C)cc1
Reactant: C#C
Agent: N
Solvent: CCOCC
Product: C#CC1(O)CCN(C)C(Cc2ccc(OC)cc2)C1(C)C
Reaction time: 16 h

Procedure:
A stream of acetylene, after successively having been washed with water, cooled to -80° C and dried with CaCl2, is led into a mechanically stirred solution of 7 g of lithium in 750 ml of dry liquid ammonia which is cooled at about -50° C. After about 5 hours the blue colour disappears. To the solution of acetylene lithium so obtained there is added dropwise 60 g of 2-(p-methoxybenzyl)-1,3,3-trimethyl-4-piperidone dissolved in 250 ml of absolute ether. During the addition a slow stream of acetylene is maintained, but afterwards this is stopped and the reaction mixture is stirred for 16 hours, the ammonia being allowed to evaporate gradually. The resulting suspension is diluted by addition of 250 ml of absolute ether and stirred for another 2 hours at 30° C. After cooling 54 g of ammonium chloride and water are added. The reaction product is secured from the organic layer in the usual manner. It is recrystallized from a mixture of benzene and petroleum ether. Yield 88%. Melting point 103°-110° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[F:10].P(Br)(Br)[Br:12].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:12])=[CH:4][C:3]=1[F:10]
Reactant: OCc1ccc(Br)c(F)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Fc1cc(CBr)ccc1Br
Temperature: 20 °C
Yield: 61 %

Procedure:
To a solution of (4-bromo-3-fluorophenyl)methanol (5 g, 24.39 mmol) in DCM (100 mL) was added PBr3 (2.76 mL, 29.3 mmol) dropwise. The resulting mixture was stirred at 20° C. After LCMS analysis showed the starting material had disappeared, the mixture was adjusted to pH=8 by aqueous Na2CO3. The organic layer was dried and concentrated to give the crude product, which was purified by column chromatography (PE/EA=10/1) to yield a white solid of 1-bromo-4-(bromomethyl)-2-fluorobenzene (4.2 g, 14.89 mmol, 61.1% yield): 1H NMR (400 MHz, CD3OD) δ 7.57 (d, J=7.6 Hz, 1H), 7.28 (d, J=7.2 Hz, 1H), 7.16 (d, J=6.4 Hz, 1H), 4.53 (s, 2H); ES-LCMS m/z 186.9 (M−79).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21](OCC)=[O:22])[N:9]=1.[NH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>O1CCCC1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([NH:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:22])[N:9]=1
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Solvent: C1CCOC1
Product: O=C(Cn1nc(-c2ccccc2O)nc1-c1ccccc1O)NCCN1CCOCC1

Procedure:
5.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) and 2.9 ml of 4-(2-aminoethyl)morpholine are boiled under reflux for 18 h in 50 ml of tetrahydrofuran. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2-morpholin-4yl-ethyl)acetamide remains as colorless crystals of m.p. 180-182° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][OH:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:26]([C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:38]=1[OH:39])[C:33](Cl)=[O:34])([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[C:40]([C:37]1[CH:36]=[C:32]([CH:31]=[C:30]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:38]=1[OH:39])[C:33]([O:19][CH2:18][CH2:17][S:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH:8]=1)=[O:34])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1cc(SCCO)cc(C(C)(C)C)c1O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(SCCOC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
A solution of 9.8 g of 2-(3,5-di-tert-butyl-4-hydroxyphenylthio) ethanol and 3.1 g of pyridine in 40 ml of toluene was added at 15°-20° C. over five minutes to a solution of 9.4 g of 3,5-di-tert-butyl-4-hydroxybenzoyl chloride in 50 ml of toluene. The reaction mixture was stirred at room temperature for 15 hours and then the resultant precipitate of triethylamine hydrochloride was removed by filtration. The solvent was removed in vacuo and the residue was recrystalized from n-heptane to give 15 g (84%) of a white solid, mp 136°-139° C.
Reaction SMILES: CCO.[OH:4][C:5]1[C:6]([C:19](=[N:38][OH:39])[CH2:20][CH2:21][C:22]2[S:23][C:24]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:25]=3[C:26]=2[CH2:27][CH2:28][CH3:29])=[CH:7][C:8]([CH3:18])=[C:9]([CH:17]=1)[O:10][CH2:11][C:12]([O:14]CC)=[O:13].O.[OH-].[Li+].Cl>O>[OH:4][C:5]1[C:6]([C:19](=[N:38][OH:39])[CH2:20][CH2:21][C:22]2[S:23][C:24]3[CH:33]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:31]=[CH:30][C:25]=3[C:26]=2[CH2:27][CH2:28][CH3:29])=[CH:7][C:8]([CH3:18])=[C:9]([CH:17]=1)[O:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCCc1c(CCC(=NO)c2cc(C)c(OCC(=O)OCC)cc2O)sc2cc(C(F)(F)F)ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1c(CCC(=NO)c2cc(C)c(OCC(=O)O)cc2O)sc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Yield: 112.9 %

Procedure:
To a mixture of EtOH (0.2 mL) and H2O (0.1 mL) was suspended ethyl 5-hydroxy-4-[1-hydroxyimino-3-[3-propyl-6-(trifluoromethyl)-benzothiophen-2-yl]propyl]-2-methylphenoxyacetate (7.5 mg, 0.0143 mmol) obtained above. After the addition of lithium hydroxide monohydrate (1.8 mg, 0.0429 mmol), the mixture was heated for 1 hour under reflux, and then allowed to cool to room temperature and added ice-water. The mixture was acidified by addition of 1M HCl, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (8.0 mg, yield>99%) as a brown crystal.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][N:3]=1.[OH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>[Pd].COCCOC>[OH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)ncc2-c2ccccc2)C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)ncc2-c2ccccc2)C1
Yield: 88.4 %

Procedure:
A mixture of (S)-tert-butyl 3-(2-chloro-5-phenylpyrimidin-4-ylamino)pyrrolidine-1-carboxylate (0.153 g, 0.408 mmol), 2-hydroxyphenylboronic acid (0.169 g, 1.24 mmol), palladium catalyst (0.013 g, 0.020 mmol) and 1 M aqueous Na2CO3 (0.82 mL, 0.82 mmol) in DME (4 mL) was refluxed for 24 hours. After cooling, water (50 mL) was added and the aqueous phase was extracted with diethyl ether (3×50 mL). The combined organic extracts were dried (MgSO4) and concentrated. The crude product was purified by silica gel chromatography (40% ethyl acetate/hexanes) to give the title compound as an oil (0.156 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.CC[N:24]([CH:28]([CH3:30])C)[CH:25]([CH3:27])C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.N1CCCC1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:15][CH:16]([C:18]([N:24]3[CH2:25][CH2:27][CH2:30][CH2:28]3)=[O:19])[CH2:17]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: O=C(C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1)N1CCCC1
Reaction time: 1.5 h

Procedure:
A 2-L 3-neck RB flask, equipped a mechanical stirrer, addition funnel and nitrogen gas inlet was charged with Intermediate 9, 3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-3-hydroxycyclobutanecarboxylic acid (0.135 mol, crude material from the above intermediate), 500 mL of anhydrous THF and DIEA (34.8 g, 0.27 mol). The initially insoluble mixture was stirred for 1.5 h until a uniform suspension formed. Then 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (50% solution in EtOAc, 104.5 mL, 0.164 mol) was added and stirred for 5 min. (NOTE: exotherm was observed, reached ˜45-50° C.). Then pyrrolidine (28.2 mL, 24.0 g, 0.337 mol) was added. (NOTE: more exotherm was observed, reached ˜70-80° C.). The mixture was stirring at RT for 12 h, then evaporated. The residue was mixed with 500 mL of sat. Na2CO3 and 200 mL of water. The mixture was extracted with DCM (5×300 mL), the extract was dried over Na2SO4, evaporated and dried to give 33.4 g (71% for two steps) of pure title compound (LCMS (M+H): 347.1. 1H NMR (300 MHz, CDCl3): δ 7.37 (t, J=7.37 Hz, 1H), 7.17-7.26 (m, 2H), 3.68 (s, 2H), 3.53 (t, J=6.78 Hz, 2H), 3.44 (t, J=6.58 Hz, 2H), 3.03-3.14 (m, 1H), 2.79-2.87 (m, 2H), 2.5-2.6 (m, 6H), 1.87-2.00 (m, 4H), 1.75-1.80 (m, 4H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)[N:28]=[N:27]C=2C=1.O.NN>ClCCl>[O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([NH:27][NH2:28])=[O:8]
Reactant: O=C(O)[C@@H]1CCCO1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: ClCCl
Solvent: O
Product: NNC(=O)[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 160.2 %

Procedure:
To a round-bottom flask was added a solution of (S)-tetrahydrofuran-2-carboxylic acid (3.00 g, 25.8 mmol, 1.00 equiv) in dichloromethane (40 mL). EDC.HCl (7.50 g, 39.1 mmol, 1.50 equiv), HOBT (5.20 g, 38.5 mmol, 1.50 equiv), and hydrazine hydrate (2 mL, 2.00 equiv, 99%) were added to the reaction. The resulting solution was stirred overnight at room temperature. The solids were removed by filtration and the filtrate was concentrated in vacuo to furnish 5.38 g (80%) of the title compound as a yellow oil.
Reaction SMILES: C([N:8]1[C:16]2[C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[C:13]([CH3:25])=[N:12][C:11]=2[NH:10][NH:9]1)C1C=CC=CC=1.C(O)(=O)C>[OH-].[OH-].[Pd+2].C(O)C>[CH3:25][C:13]1[N:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:15](=[O:17])[C:16]2[N:8]=[N:9][NH:10][C:11]=2[N:12]=1
Reactant: Cc1ccccc1-n1c(C)nc2c(c1=O)N(Cc1ccccc1)NN2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccccc1-n1c(C)nc2[nH]nnc2c1=O
Reaction time: 48 h
Yield: 16.8 %

Procedure:
A mixture of 1-benzyl-5-methyl-6-o-tolyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one (4.0 g, 12.07 mmol), acetic acid (150 mL), ethanol (25 mL), and palladium hydroxide on carbon (4.0 g) was hydrogenated on a Parr apparatus. After 5 hours the catalyst was filtered off and replaced with fresh palladium hydroxide on carbon (4.0 g). The hydrogenation was continued 48 hours longer. The reaction was filtered and the filtrate was concentrated to afford 5-methyl-6-o-tolyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7one (0.488 g, 17%) as a white powder.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[S:15])([CH3:3])[CH3:2].Cl.C([O:19][C:20](=O)[CH2:21][NH:22][CH3:23])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[N:13]1[C:20](=[O:19])[CH2:21][N:22]([CH3:23])[C:14]1=[S:15])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CNC
Reactant: CC(C)c1cccc(C(C)C)c1N=C=S
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)CN(C)C1=S
Yield: 60.2 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 8.3 g of 2,6-diisopropylphenyl-isothiocyanate, 5.8 g of sarcosine ethyl ester hydrochloride, 14.5 g of triethyl amine, and 200 mL of chloroform. Crystallization from diethyl ether/hexane mixture afforded the title compound (6.6 g) as a tan solid, m.p. 174°-176° C. Anal. Calcd. for C16H22N2OS: C, 66.17; H, 7.63; N, 9.64. Found: C, 66.39; H, 7.63; N, 9.59. Mass spectrum (+FAB, [M+H]+) m/z 269/271.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1>[CH3:16][S:17]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:8])([F:7])[F:1])(=[O:19])=[O:18]
Reactant: OCCCC(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCCC(F)(F)F

Procedure:
The 4,4,4-trifluoro-1-butanol (Lancaster, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [CH3:1][N:2]=[C:3]([NH2:18])[NH:4][C:5]1[CH:9]=[N:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[NH:17])OC)[N:6]=1.[C:19]([NH:22][NH2:23])(=[O:21])[CH3:20]>CO>[C:19]([NH:22][NH:23][C:14](=[NH:17])[CH2:13][CH2:12][CH2:11][CH2:10][N:7]1[N:6]=[C:5]([NH:4][C:3]([NH2:18])=[N:2][CH3:1])[CH:9]=[N:8]1)(=[O:21])[CH3:20]
Reactant: CC(=O)NN
Reactant: CN=C(N)Nc1cnn(CCCCC(=N)OC)n1
Solvent: CO
Product: CN=C(N)Nc1cnn(CCCCC(=N)NNC(C)=O)n1

Procedure:
Methyl 5-[4-[2-methylguanidino)-1,2,3-triazol2-yl]valerimidate (1.0 g.) in MeOH (12 ml.) was treated with acethydrazide (0.22 g.) and the solution stirred for 18 nours. Evaporation of the solvent and trituration of the resioue with ether/EtOH gave N-acetylamino-5[4-(2-methylguanidino)-1,2,3-triazol-2-yl]valeramidine as a yellow sticky solid [0.54 g.) which was used without further purification.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=O)[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>O1CCCC1>[CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Solvent: C1CCOC1
Product: c1ccc2c(c1)CNc1ccccc1N2
Temperature: 110 °C
Reaction time: 18 h
Yield: 79.7 %

Procedure:
To a stirred solution of 4.3 g of 5,11-dihydro-10H-dibenz[b,e][1,4]diazepin-11-one in 50 ml of tetrahydrofuran, under nitrogen and cooled to 0° C. is added 4.0 ml of a 10 molar solution of dimethyl sulfide-borane complex in tetrahydrofuran. The ice bath is removed after 30 minutes and the reaction mixture stirred at room for 18 hours. The reaction mixture is cooled in an ice bath and 30 ml of anhydrous methanol added dropwise and evaporated to dryness in vacuo. Another 30 ml of methanol is added and evaporated to a residue. The residue is quenched with 30 ml of 40% sodium hydroxide followed by heating at 110° C. for 45 minutes and cooling to room temperature. The reaction mixture is diluted with 200 ml of water and extracted with methylene chloride (3×100 ml). The combined extracts are washed with 1N HCl, water and 0.5N NaOH. The organic layer is dried and evaporated in vacuo to give 3.2 g of the desired product, m.p. 114°-116° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9]C=O)=[C:4]([Cl:12])[N:3]=1.C(O)C>Cl>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[C:4]([Cl:12])[N:3]=1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Agent: Cl
Solvent: CCO
Product: Nc1nc(Cl)c(N)c(Cl)n1
Yield: 64.6 %

Procedure:
N-(2-Amino-4,6-dichloro 5-pyrimidinyl)formamide (Example 3, 500 mg, 2.42 mmol) was dissolved in 0.1 N hydrochloric acid (5 mL, 2.5 mequiv) and ethanol (7 mL) at reflux. The solution was refluxed for 5 hours. Volatiles were removed in vacuo. The residue was partitioned between water (30 mL) adjusted to pH 8 with dilute ammonium hydroxide and ethyl acetate (75 mL). The ethyl acetate layer was dried (sodium sulfate). Evaporation of the ethyl acetate left pink solid (0.40 g). Recrystallization of the solid from 95% ethanol gave the title compound (IV) as light pink needles (280 mg, 65%); darkens and shrinks to black solid above 85° C., does not become fluid below 300° C.; 1H-NMR (DMSO-d6) and mass spectra identical to those described in Example 4.
Reaction SMILES: [CH2:1]([C:5]1([C:18]([O:20][CH3:21])=[O:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH:7]=[C:6]1[O:16]C)[CH2:2][CH2:3][CH3:4].I[Si](C)(C)C>C(#N)C>[CH2:1]([C:5]1([C:18]([O:20][CH3:21])=[O:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH2:7][C:6]1=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(C(=O)OC)C(OC)=CC(=O)c2ccccc21
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CCCCC1(C(=O)OC)C(=O)CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of Example 167B (1 g, 3.5 mmol) in acetonitrile (5 mL) was added iodotrimethylsilane (TMSI) (0.7 mL, 5.2 mmol). The reaction solution was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo. Column chromatography on silica (ethyl acetate) afforded the title compound as a white solid (0.88 g, 92%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.47 (m, 1H), 0.68 (t, J=7.35 Hz, 3H), 0.85 (dd, J=12.32, 7.17 Hz, 1H), 1.11 (m, 2H), 2.14 (m, 1H), 2.29 (m, 1H), 3.51 (s, 3H), 5.74 (m, 1H), 7.31 (m, 1H), 7.49 (m, 1H), 7.58 (t, J=7.17 Hz, 1H), 7.93 (d, J=7.35 Hz, 1H), 12.11 (s, 1H); MS (ESI) m/z 275.0 (M+H)+.