Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3][CH3:4].[Mg].[C:7]([P:11](Cl)[C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])([CH3:9])[CH3:8].S(=O)(=O)(O)O>O1CCCC1.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Cu].C1(C)C=CC=CC=1>[C:7]([P:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:1][CH2:2][CH2:3][CH3:4])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCCCCl
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: [Cu]
Agent: CC(=O)/C=C(/C)O
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCP(C(C)(C)C)C(C)(C)C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
In a 300 ml four-necked flask thoroughly purged with nitrogen, a Grignard reagent solution previously prepared from 5.6 g (0.060 mol) of n-butyl chloride and 1.7 g (0.072 mol) of metallic magnesium in 100 ml of tetrahydrofuran, and 0.13 g (0.0005 mol (corresponding to 1% by mol)) of copper(II) acetylacetonate were placed. To the contents of the flask, a solution of 9.0 g (0.05 mol) of di-tert-butylphosphinous chloride in 30 ml of tetrahydrofuran was dropwise added over a period of 1 hour with maintaining the temperature at 20° C. to 25° C. After the dropwise addition was completed, stirring was conducted at the same temperature for 2 hours. Thereafter, 30 ml of toluene and 20 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by further distillation. Then, fractions given by distillation at 111° C. under reduced pressure of 19 Torr were collected. As a result, 9.4 g (purity: 98.0%) of the aimed di-tert-butyl(n-butyl)phosphine was obtained. The yield was 91.1%.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([C:14]2[CH:15]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:17]=[CH:18][CH:19]=2)=[CH:3][CH:2]=1.[Br:29][C:30]1[CH:31]=[C:32]([Si:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:33]=[C:34](Br)[CH:35]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:29][C:30]1[CH:31]=[C:32]([Si:37]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:33]=[C:34]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:4]3[C:5]4[S:6][C:7]5[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=5[C:9]=4[CH:1]=[CH:2][CH:3]=3)[CH:15]=2)[CH:35]=1
Reactant: CC1(C)OB(c2cccc(-c3cccc4c3sc3ccccc34)c2)OC1(C)C
Reactant: Brc1cc(Br)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cc(-c2cccc(-c3cccc4c3sc3ccccc34)c2)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A solution of 2-(3-(dibenzo[b,d]thiophen-4-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.00 g, 5.18 mmol), (3,5-dibromophenyl)triphenylsilane (5.12 g, 10.35 mmol), Pd(PPh3)4 (0.120 g, 0.104 mmol), K2CO3 (2.147 g, 15.53 mmol) in toluene (100 mL) and water (20 mL) was refluxed under nitrogen overnight. After cooling to room temperature, the organic phase was isolated, and the solvent was evaporated. The residue was purified by column chromatography on silica gel with hexane/DCM (2/1 v/v) as eluent to yield (5-bromo-3′-(dibenzo[b,d]thiophen-4-yl)-[1,1′-biphenyl]-3-yl)triphenylsilane (2.8 g, 80% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 5-bromosalicylaldehyde (5.00 g) and potassium carbonate (10.3 g) in N,N-dimethylformamide (50 ml) was added octyl bromide (4.52 ml), and the mixture was stirred at room temperature for 1.5 hr, and further at 50° C. for 3.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine 3 times, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (7.72 g) as a white solid.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[O:19]([CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:28]1[CH2:29][CH2:30][CH:26]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:27]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: c1ccc(OC2CCNC2)cc1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCc2cc(/C=C/C(=O)N3CCC(Oc4ccccc4)C3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 3-phenoxypyrrolidine hydrochloride (28 mg, 0.14 mmol; which may be prepared as described in Step 3), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on preparative TLC (eluent: dichloromethane/NH3 7N in MeOH, 2.5%) to give a pale yellow solid. This solid was triturated in methanol, filtered, washed with methanol, acetone and diethyl ether then dried to give the title compound (30 mg, 68%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[CH:7]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:13]>C1C=CC=CC=1.CO>[Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([C:8]([O:10][CH3:13])=[O:9])[CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cnc(O)c(Cl)c1
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1cnc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
To a stirred solution of 3-chloro-2-hydroxypyridine-5-carboxylic acid (1 g, 5.762 mmol) in benzene (16 mL) and MeOH (4 mL) was added dropwise TMSCHN2 (3.17 mL, 6.338 mmol) at 0° C., and the resulting mixture was stirred overnight at room temp. The reaction mixture was quenched by the addition of AcOH and the mixture was evaporated off. The residue was suspended in water and precipitate was collected. The crude solid was washed with Et2O, and dried under a reduced pressure to give 728.1 mg (67%) methyl 3-chloro-2-hydroxypyridine-5-carboxylate as a white crystalline powder. IR (KBr) 1655, 1282, 1245, 769 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ3.79 (s, 3H), 8.01 (s, 1H), 8.06 (s, 1H); MS (FAB) m/z 188 (M++1); Anal. Calcd. for C7H6ClNO3: C, 44.82; H, 3.22; Cl, 18.90; N, 7.47. Found: C, 44.74; H, 3.22; Cl, 19.00; N, 7.34.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.[CH:41]1([NH:44][NH2:45])[CH2:43][CH2:42]1.CCN(C(C)C)C(C)C>O.C(Cl)Cl>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:45][NH:44][CH:41]3[CH2:43][CH2:42]3)=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NNC1CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNC1CC1
Reaction time: 1 h
Yield: 2.7 %

Procedure:
A 100-mL, 3-necked, round-bottomed flask was charged with (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.50 g.) and CH2Cl2 (25 mL). DCC (0.29 g, 1.0 eq.) was added and the mixture was cooled to 0° C. for the sequential addition of cyclopropylhydrazine hydrochloride (0.15 g, 1.0 eq.) and DIPEA (0.24 mL, 1.0 eq.). The reaction mixture was stirred for 1 h before being poured into water (50 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure (25° C., 20 mmHg) to afford crude compound. Purification by combi-flash chromatography (elution with 1.5-2.5% MeOH in CH2Cl2) followed by further purification on a preparative TLC plate (eluting with 70% EtOAc in hexane) afforded 15 mg (yield: 2.6%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-cyclopropylacrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ, 9.16 (s, 1H), 8.52 (s, 1H), 8.28 (s, 1H), 7.23-7.26 (d, J=10.4 Hz, 1H), 6.40-6.43 (d, J=10.4 Hz, 1H), 4.97 (s, 1H), 4.63 (s, 1H), 3.18-3.20 (m, 1H), 0.83-0.87 (m, 2H), 0.65-0.69 (m, 2H); LCMS for Chemical Formula: C16H14F6N5O [M+H]+ 406.31. found 406.19 (RT 2.74 min, purity: 98.85%).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[CH2:12]([NH:15][C:16]([NH2:18])=[O:17])[CH:13]=[CH2:14].CC(N=NC(C#N)(C)C)(C#N)C>>[Si:5]([CH2:4][CH2:3][CH2:2][S:1][CH2:14][CH2:13][CH2:12][NH:15][C:16]([NH2:18])=[O:17])([O:10][CH3:11])([O:6][CH3:7])[O:8][CH3:9]
Reactant: CO[Si](CCCS)(OC)OC
Reactant: C=CCNC(N)=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CO[Si](CCCSCCCNC(N)=O)(OC)OC
Temperature: 90 °C

Procedure:
70 grams of mercaptopropyltrimethoxy silane and 35.5 gms. of allylurea were weighed into a flask equipped as in Example 1. The contents of the flask were heated to about 90° C. and 0.3 gm. of Vazo 64 was used. The temperature indicated an exotherm to about 145° C. which was controlled back down to about 100° C. for a total of 6® hours and it was then cooled. Titration of a sample showed about 71% reaction of the mercaptan. The material was filtered. The proton NMR analysis showed a structure consistent with the title compound. There was unreacted allylurea present at less than 25%.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH2:18]([O:25][CH:26]1[CH2:29][C:28](=O)[CH2:27]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[CH2:18]([O:25][CH:26]1[CH2:29][C:28](=[CH:9][C:7]#[N:8])[CH2:27]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CC(OCc2ccccc2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=C1CC(OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To a mixture of 1.0000 M of potassium tert-butoxide in tetrahydrofuran (0.68 mL) and THF (5 mL) was added, at 0° C., diethyl cyanomethylphosphonate (0.11 mL, 0.00068 mol) dropwise. The reaction was warmed to rt and 30 min later cooled to 0° C. again. To the reaction mixture was added a solution of 3-(benzyloxy)cyclobutanone (0.1 g, 0.0006 mol) in THF (5 mL). The reaction was stirred over night, allowing warmed up to rt. The reaction was quenched with saturated aq. NH4Cl solution, extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated to dryness. The crude product was used directly in next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][C:23]1[C:35]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:34][C:26]2[O:27][C:28]([C:31](O)=[O:32])=[CH:29][O:30][C:25]=2[CH:24]=1>>[OH:22][C:23]1[C:35]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:34][C:26]2[O:27][C:28]([C:31]([N:12]3[CH2:11][CH2:10][N:9]([CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH2:14][CH2:13]3)=[O:32])=[CH:29][O:30][C:25]=2[CH:24]=1
Reactant: CC(C)(C)c1cc2c(cc1O)OC=C(C(=O)O)O2
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Product: CC(C)(C)c1cc2c(cc1O)OC=C(C(=O)N1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)O2
Yield: 83 %

Procedure:
That compound is obtained in a yield of 83% starting from 1-[bis-(4-fluorophenyl)methyl]piperazine and 6-hydroxy-7-tert-butyl-1,4-benzodioxin-2-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)C.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]>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: COc1ccc(N)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2cncc(Br)c2)cc1
Temperature: 70 °C

Procedure:
A mixture of 3,5-dibromopyridine (1.5 g, 6.3 mmol), p-anisidine (0.94 g, 7.60 mmol), (R)-(+)-2,2′-bis(diphenyl-phosphino)-1,1′-binapthyl (0.16 g, 0.25 mmol) and sodium tert-butoxide (0.85 g, 8.86 mmol) in toluene (15 ml) is deoxygenated using argon before adding Pd2(dba)3 (0.116 g, 0.13 mmol) and heating the mixture at 70° C. for 16 hours. The mixture is diluted with diethyl ether, washed with brine, dried over Na2SO4 and concentrated. The residue is chromatographed on silicagel to afford the product; 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J=2.42 Hz, 1H), 8.04 (d, J=1.82 Hz, 1H), 7.30 (m, 1H), 7.09 (m, 2H), 6.90 (m, 2H), 5.89 (s, 1H), 3.81 (s, 3H).
Reaction SMILES: CC1[C@@H:8]2[C:9](C)([CH3:10])[C@@H:6]([CH2:7]2)[C:4](=[O:5])[CH:3]=1.C(#N)C.O.CC[O:18][C:19]([CH3:21])=[O:20]>C(Cl)(Cl)(Cl)Cl>[C:4]([C@@H:6]1[CH2:7][C@H:21]([C:19]([OH:18])=[O:20])[C:9]1([CH3:10])[CH3:8])(=[O:5])[CH3:3]
Reactant: CC1=CC(=O)[C@@H]2C[C@H]1C2(C)C
Reactant: CCOC(C)=O
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)[C@@H]1C[C@H](C(=O)O)C1(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A stirred solution of verbenone (about 10 g, 66.57 mmol) in CCl4: ACN: H2O (140 ml) NaIO4 (56.9 g, 266.3 mmol) followed by RuCl3.H2O (catalytic) were added at 0° C. and allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), reaction mixture was diluted with EtOAc (about 200 ml), filtered through celite bed and the organic layer was separated, the aqueous layer extracted with EtOAc (100 ml×2) combined the organic layers dried with Na2SO4 and concentrated under reduced pressure. The resulting crude was stirred in hexane. Solid was filtered and dried under vacuum (8.56 g). 1H NMR (300 MHZ, CDCl3): δ 2.91-2.77 (m, 2H), 2.63 (q, 1H, J=9 Hz), 2.07 (s, 3H), 1.86-1.95 (m, 1H), 1.40 (s, 3H), 0.97 (s, 3H). Mass: [M+1]+ 171 (10%), [M+Na]+ 193 (72%). IR (KBr, cm−1): 3218, 1737, 1694, 1467, 1368, 1283, 1174, 1080, 836, 703. M.R: 109.5° C.-120.7° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([NH2:17])=[NH:16])[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[C:20]1([C:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=O)=O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:26]2[N:16]=[C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:4]4[C:3]([C:2]([F:1])([F:18])[F:19])=[CH:8][CH:7]=[CH:6][N:5]=4)[CH2:10][CH2:11]3)[NH:17][C:28]=2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N=C(N)N1CCN(c2ncccc2C(F)(F)F)CC1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Product: FC(F)(F)c1cccnc1N1CCN(c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)CC1

Procedure:
4-(3-(Trifluoromethyl)pyridin-2-yl)piperazine-1-carboxamidine (300 mg, 1.10 mmol, Example 3(a)) reacted with benzil (231 mg, 1.10 mmol, Aldrich) under the conditions of Example 4(b). The crude product was purified by silica gel column chromatography (1:3 EtOAc/hexane) to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 450.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[C:9]([CH3:23])([CH3:22])[C:10]([NH:12][C:13]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[O:15][N:14]=1)=[O:11]>C1COCC1>[CH2:1]([NH:5][C:9]([CH3:23])([CH3:22])[C:10]([NH:12][C:13]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[O:15][N:14]=1)=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)on1
Reactant: CCCCN
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCNC(C)(C)C(=O)Nc1cc(C(C)(C)C)on1
Reaction time: 16 h
Yield: 35.9 %

Procedure:
To a solution of n-butylamine (51 mg, 0.69 mmol) in THF (2 mL) at room temperature under nitrogen is added NaH (33 mg, 1.38 mmol) in portions over 10 min. After the addition is complete, 2-bromo-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-propionamide (0.10 g, 0.35 mmol) is introduced to the reaction and the resulting mixture is stirred for 16 h. The solvent is then removed under reduced pressure and the residue is partitioned between DCM and saturated aqueous NaHCO3 solution. The organic phase is separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The crude product is purified by mass-triggered preparative HPLC. The purified compound is dissolved in DCM and free-based with Ambersep 900-OH resin over 2 h. After this time, the suspension is filtered and the filtrate is concentrated under reduced pressure to provide the title compound (35.4 mg, 37%).
Reaction SMILES: [N:1]([CH2:8][CH2:9][OH:10])([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].N1C=CC=CC=1.Cl[C:18]([C:20]1[C:32]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[C:33]([C:36]#[N:37])[C:34]#[N:35])[C:24]=2[CH:23]=[CH:22][CH:21]=1)=[O:19]>ClCCl>[C:36]([C:33]([C:34]#[N:35])=[C:25]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:18]([O:4][CH2:3][CH2:2][N:1]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7])=[O:19])[C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)#[N:37]
Reactant: N#CC(C#N)=C1c2ccccc2-c2c(C(=O)Cl)cccc21
Reactant: OCCN(CCO)CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#CC(C#N)=C1c2ccccc2-c2c(C(=O)OCCN(CCO)CCO)cccc21

Procedure:
A solution of 100.0 grams of triethanolamine and 58 milliliters of dry pyridine in 350 milliliters of dry dichloromethane was stirred at room temperature under a nitrogen atmosphere. A solution of 8.0 grams of (4-chloroformyl-9-fluorenylidene)malononitrile in 400 milliliters of dry dichloromethane was added over a period of 1 hour. After addition, the reaction mixture was further stirred for another hour. The reaction mixture was washed several times with water to remove the excess amines and the corresponding hydrochloride salts, dried with anhydrous magnesium sulfate and filtered. Evaporation of the filtrate gave 5 grams of crude product. Purification by recrystallization from isopropanol afforded 4.5 grams of pure (1c), mp., 155.5°-156.5° C.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH:6][NH2:7])=[NH:5].C[O-].[Na+].CC[O:13][C:14]([CH:16]([C:18]([CH3:20])=O)[CH3:17])=O>C(O)C>[NH2:2][N:3]1[C:14](=[O:13])[C:16]([CH3:17])=[C:18]([CH3:20])[N:5]=[C:4]1[NH:6][NH2:7]
Reactant: N=C(NN)NN
Reactant: CCOC(=O)C(C)C(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(NN)n(N)c(=O)c1C
Yield: 53.3 %

Procedure:
A mixture of 13.22 g of diaminoguanidine hydrochloride, 5.4 g of sodium methoxide, 7.2 g of ethyl-2-methyl acetoacetate and 100 ml of ethanol was reacted as described in Example 1, giving 4.5 g of 3-amino-2-hydrazino-5,6-dimethyl-4(3H)-pyrimidinone.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[N:16][CH:17]=2)=[O:9])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([N:42]3[CH2:46][CH2:45][CH2:44][C:43]3=[O:47])=[N:40][CH:41]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:47]=[C:43]1[CH2:44][CH2:45][CH2:46][N:42]1[C:39]1[N:40]=[CH:41][C:36]([C:2]2[CH:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)=[N:16][CH:17]=3)=[O:9])=[CH:4][CH:3]=2)=[CH:37][CH:38]=1
Reactant: O=C(NCc1ccc(-c2ccnc(C(F)(F)F)c2)nc1)c1ccc(Br)cn1
Reactant: CC1(C)OB(c2ccc(N3CCCC3=O)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCc1ccc(-c2ccnc(C(F)(F)F)c2)nc1)c1ccc(-c2ccc(N3CCCC3=O)nc2)cn1
Temperature: 96 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-N-((2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methyl)picolinamide 72-1 (22 mg, 0.05 mmol), 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrrolidin-2-one 72-2 (29 mg, 0.1 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol) and K3PO4 (21 mg, 0.1 mmol) in dioxane (0.5 mL) and water (0.1 mL) was stirred at 96° C. under argon overnight. After cooling to room temperature, the mixture was filtered through celite (washed with ethyl acetate) and the filtrate was redistributed between ethyl acetate and water. The organic phase was dried over Na2SO4 and concentrated with rotavap. The residue was subjected to preparative reverse phase HPLC separation to give 6′-(2-oxopyrrolidin-1-yl)-N-((2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methyl)-[3,3′-bipyridine]-6-carboxamide 72 as a solid. MS m/z 519.2 (M+1). 1H NMR 400 MHz (CDCl3) δ 8.83 (d, 1H), 8.79 (d, 1H), 8.76 (dd, 1H), 8.62 (dd, 1H), 8.57 (dd, 1H), 8.52 (t, 1H), 8.34-8.29 (m, 2H), 8.10-8.02 (m, 2H), 7.96-7.88 (m, 2H), 7.84 (d, 1H), 4.79 (d, 2H), 4.16 (t, 2H), 2.71 (t, 2H), 2.18 (t, 2H).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[NH2:12][C@H:13]1[CH2:16][O:15][C:14]1=[O:17].[NH:18]1[CH:22]=[CH:21][CH:20]=[N:19]1>CN(C=O)C>[N:18]1([CH2:16][C@@H:13]([C:14]([OH:15])=[O:17])[NH2:12])[CH:22]=[CH:21][CH:20]=[N:19]1
Reactant: N[C@H]1COC1=O
Reactant: c1cn[nH]c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: N[C@@H](Cn1cccn1)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.3 %

Procedure:
(S)-3-Amino-2-oxetanone tosylate salt (100 mg, 0.385 mmol) was added to pyrazole (131 mg, 1.93 mmol) in distilled DMF (3.0 mL) and the mixture was stirred at 25° C. for 2.5 h. The solvent was removed in vacuo at 25° C. and the residue was dissolved in H2O (3 mL) and applied to a column of BioRad AG50-X8 (trademark) (1×10 cm, H+ form) The resin was washed with H2O (30 mL) and eluted with a gradient of aqueous NH4OH (0 to 0.25N over 70 mL, then 100 mL of 0.25N NH4OH). The product emerged chromatographically pure with 0.25N NH4OH and was lyophilized (2×) and dried in vacuo over P2O5 to yield 77% (46.2 mg) of β-(pyrazol-1-yl)-L-alanine (mp 234°-236° C. (dec)). For an improved melting point this material could be recrystallized from H2O/ EtOH: mp 241°-243° C. (lit. mp 236°-238° C. (dec), 243° C. (dec)); [α]D25 -72(±1) (c 0.54, H2O) (lit. [α]D -78° (c 3.4, H2O),-72.0° (c 1. H2O)); IR (KBr disk) 3700-2200 (m, vbr), 1617 (s), 1580 (s), 1485 (m), 1395 (m), 767 (m) cm-1 ; 1H NMR (300 MHz, D2O)δ 7.65 (d, 1H, 2 Hz, ArHH'H"), 7.61 (d, 1H, 2 Hz, ArHH'H"), 6.38 (t, 1H, 2 Hz, ArHH'H"), 4.66 (d, 2H, 5 Hz, CH2N), 4.18 (t, 1H, 5 Hz, CH); POSFAB-MS glycerol/HC1 ) 156 (MH+), 311 (M2H+); Rf 0.67 (Solvent A; characteristic blue-purple color with ninhydrin).